Compounds For the Treatment of HIV

ABSTRACT

The invention provides compounds of formula (I): or a salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of formula (I), processes for preparing compounds of formula (I), intermediates useful for preparing compounds of formula I and therapeutic methods for treating a Retroviridae viral infection including an infection caused by the HIV virus.

CROSS REFERENCE TO RELATED APPLICATION

This patent application claims the benefit of priority of U.S.application Ser. No. 61/505,032 filed Jul. 6, 2011, which application ishereby incorporated by reference.

BACKGROUND OF THE INVENTION

Positive-single stranded RNA viruses comprising the Retroviridae familyinclude those of the subfamily Orthoretrovirinae and generaAlpharetrovirus, Betaretrovirus, Gamaretrovirus, Deltaretrovirus,Epsilonretrovirus, Lentivirus, and Spumavirus which cause many human andanimal diseases. Among the Lentivirus, HIV-1 infection in humans leadsto depletion of T helper cells and immune dysfunction, producingimmunodeficiency and vulnerability to opportunistic infections. TreatingHIV-1 infections with highly active antiretroviral therapies (HAART) hasproven to be effective at reducing viral load and significantly delayingdisease progression (Hammer, S. M., et al.; JAMA 2008, 300: 555-570).However, these treatments do lead to the emergence of HIV strains thatare resistant to current therapies (Taiwo, B., International Journal ofInfectious Diseases 2009, 13:552-559; Smith, R. J., et al., Science2010, 327:697-701). Therefore, there is a pressing need to discover newantiretroviral agents that are active against emerging drug-resistantHIV variants.

SUMMARY OF THE INVENTION

The present invention provides compounds and methods for the treatmentof an HIV infection. In one embodiment, the invention provides acompound of the invention which is a compound of formula I:

wherein:

A is a 6-membered heteroaryl comprising one or two nitrogens, whereinthe 6-membered heteroaryl is substituted with one Z¹ group andoptionally substituted with one or more (e.g. 1, 2, or 3) Z² groups;

B is absent; or B is —O— and the nitrogen to which the —O⁻ group isattached is N⁺;

W is —CR^(3a)R^(3b)—, —O—, —NR⁴—, —OCR^(3a)R^(3b)— or absent;

R¹ is aryl, heteroaryl or heterocycle, wherein any aryl, heteroaryl orheterocycle of R¹ is optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z³ groups;

R² is a 6-membered aryl, 5-membered heteroaryl or 6-membered heteroaryl,wherein any 6-membered aryl, 5-membered heteroaryl or 6-memberedheteroaryl of R² is optionally substituted with one or more (e.g. 1, 2or 3) Z⁴ groups;

each R^(3a) and R^(3b) is independently selected from H, halogen,(C₁-C₆)alkyl, (C₃-C₇)carbocycle, (C₁-C₃)haloalkyl, (C₁-C₆)heteroalkyl,heteroaryl(C₁-C₆)alkyl-, heterocyclyl(C₁-C₆)alkyl-, —NR_(a)R_(b), and—NR_(c)COR_(d), wherein any (C₁-C₆)alkyl of R^(3a) and R^(3b) isoptionally substituted with one or more OH groups; or R^(3a) and R^(3b)together with the carbon to which they are attached form a(C₃-C₆)carbocycle;

R⁴ is selected from H, (C₁-C₆)alkyl, (C₃-C₆)carbocycle,aryl(C₁-C₆)alkyl- and heteroaryl(C₁-C₆)alkyl-;

R_(a) and R_(b) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R_(a) and R_(b) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

each R_(c) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R_(d) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl, aryl,haloaryl, haloheteroaryl, haloheterocycle, (C₁₋C₈)haloalkyl and(C₁-C₈)heteroalkyl;

each Z¹ is independently selected from (C₂-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, aryl, heteroaryl, heterocycle and—OR_(n1), wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of Z¹ is optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z^(1a) or Z^(1b) groups and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of Z¹ is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z^(1a) groups;

each Z^(1a) is independently selected from (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n2), —OC(O)R_(p2),—OC(O)NR_(q2)R_(r2), —SR_(n2), —S(O)R_(p2), —S(O)₂OH, —S(O)₂R_(p2),—S(O)₂NR_(q2)R_(r2), —NR_(q2)R_(r2), —NR_(n2)COR_(p2),—NR_(n2)CO₂R_(p2), —NR_(n2)CONR_(q2)R_(r2), —NR_(n2)S(O)₂R_(p2),—NR_(n2)S(O)₂OR_(p2), —NR_(n2)S(O)₂NR_(q2)R_(r2), NO₂, —C(O)R_(n2),—C(O)OR_(n2), —C(O)NR_(q2)R_(r2) and —S(O)₂NR_(n2)COR_(p2), wherein any(C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle of Z^(1a) isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(1c) orZ^(1d) groups;

each Z^(1b) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl, wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z^(1b) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(1c) groups;

each Z^(1c) is independently selected from (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n3), —OC(O)R_(p3),—OC(O)NR_(q3)R_(r3), —SR_(n3), —S(O)R_(p3), —S(O)₂OH, —S(O)₂R_(p3),—S(O)₂NR_(q3)R_(r3), —NR_(q3)R_(r3), —NR_(n3)COR_(p3),—NR_(n3)CO₂R_(p3), —NR_(n3)CONR_(q3)R_(r3), —NR_(n3)S(O)₂R_(p3),—NR_(n3)S(O)₂OR_(p3), —NR_(n3)S(O₂NR_(q3)R_(r3), NO₂, —C(O)R_(n3),—C(O)OR_(n3), —C(O)NR_(q3)R_(r3), haloaryl, haloheteroaryl,haloheterocycle and (C₁-C₈)heteroalkyl;

each Z^(1d) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl and (C₁-C₈)haloalkyl;

each R_(n1) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and aryl,wherein any (C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle ofR_(n1) is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(1a) or Z^(1b) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of R_(n1) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(1a) groups;

each R₂ is independently selected from H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and aryl,wherein any (C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle ofR_(n2) is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(1c) or Z^(1d) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of R_(n2) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(1c) groups;

each R_(p2) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and aryl,wherein any (C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle ofR_(p2) is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(1c) or Z^(1a) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of R_(p2) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(1c) groups;

R_(q2) and R_(r2) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(q2) or R_(r2) is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) d groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(q2) or R_(r2) isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(1c)groups, or R_(q2) and R_(r2) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups;

each R_(n3) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R_(p3) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl, aryl,haloaryl, haloheteroaryl, haloheterocycle, (C₁-C₈)haloalkyl and(C₁-C₈)heteroalkyl;

R_(q3) and R_(r3) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R_(q3) and R_(r3) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

each Z² is independently selected from (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,(C₃-C₇)carbocycle, halogen, CN, OH and —O(C₁-C₆)alkyl;

each Z³ is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, aryl, heteroaryl, heterocycle,halogen, —CN, —OR_(n4), —OC(O)R_(p4), —OC(O)NR_(q4)R_(r4), —SR_(n4),—S(O)R_(p4), —S(O)₂OH, —S(O)₂R_(p4), —S(O)₂NR_(q4)R_(r4),—NR_(q4)R_(r4), —NR_(n4)COR_(p4), —NR_(n4)CO₂R_(p4),—NR_(n4)CONR_(q4)R_(r4), —NR_(n4)S(O)₂R_(p4), —NR_(n4)S(O)₂OR_(p4),—NR_(n4)S(O)₂NR_(q4)R_(r4), NO₂, —C(O)R_(n4), —C(O)OR_(n4),—C(O)NR_(q4)R_(r4) and —B(OR_(q4))(OR_(r4)) wherein any(C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle of Z³ is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(3a) or Z^(3b)groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynylof Z³ is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(3a) groups;

each Z^(3a) is independently selected from (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n5), —OC(O)R_(p5),—OC(O)NR_(q5)R_(r5), —SR_(n5), —S(O)R_(p5), —S(O)₂OH, —S(O)₂R_(p5),—S(O)₂NR_(q5)R_(r5), —NR_(q5)R_(r5), —NR_(n5)COR_(p5),—NR_(n5)CO₂R_(p5), —NR_(n5)CONR_(q5)R_(r5), —NR_(n5)S(O)₂R_(p5),—NR_(n5)S(O)₂OR_(p5), —NR_(n5)S(O)₂NR_(q5)R_(r5), NO₂, —C(O)R_(n5),—C(O)OR_(n5), and —C(O)NR_(q5)R_(r5), wherein any (C₃-C₇)carbocycle,aryl, heteroaryl and heterocycle of Z^(3a) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(3c) or Z^(3d) groups;

each Z^(3b) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl, wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z^(3b) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(3c) groups;

each Z^(3c) is independently selected from (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n6), —OC(O)R_(p6),—OC(O)NR_(q6)R_(r6), —SR_(n6), —S(O)R_(p6), —S(O)₂OH, —S(O)₂R_(p6),—S(O)₂NR_(q6)R_(r6), —NR_(q6)R_(r6), —NR_(n6)COR_(p6), —NR₆CO₂R_(p6),—NR_(n6)CONR_(q6)R_(r6), —NR_(n6)S(O)₂R_(p6), —NR_(n6)S(O)₂OR_(p6),—NR_(n6)S(O)₂ NR_(q6)R_(r6), NO₂, —C(O)R_(n6), —C(O)OR_(n6),—C(O)NR_(q6)R_(r6), haloaryl, haloheteroaryl, haloheterocycle and(C₁-C₈)heteroalkyl;

each Z^(3d) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, and (C₁-C₈)haloalkyl;

each R_(n4) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(n4) is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(3a) or Z^(3b) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(n4) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(3a) groups;

each R_(p4) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and aryl,wherein any (C₃-C₇)carbocycle, aryl, heteroaryl, or heterocycle ofR_(p4) is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(3a) or Z^(3b) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl or(C₂-C₈)alkynyl of R_(p4) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(3a) groups;

R_(q4) and R_(r4) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(q4) or R_(r4) is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(3a) or Z^(3b) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(q4) or R_(r4) isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(3a)groups, or R_(q4) and R_(r4) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(3a) or Z^(3b) groups;

each R_(n5) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(n5) is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(3c) or Z^(3d) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(n5) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(3c) groups;

each R_(p5) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and aryl,wherein any (C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle ofR_(p5) is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(3c) or Z^(3d) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of R_(p5) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(3c) groups;

R_(q5) and R_(r5) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(q5) or R_(r5) is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(3c) or Z^(3d) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(q5) or R_(r5) isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(3c)groups, or R_(q5) and R_(r5) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(3c) or Z^(3d) groups;

each R_(n6) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R_(p6) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl, aryl,haloaryl, haloheteroaryl, haloheterocycle, (C₁₋C₈)haloalkyl and(C₁-C₈)heteroalkyl;

R_(q6) and R_(r6) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R_(q6) and R_(r6) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

each Z⁴ is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, aryl, heteroaryl, heterocycle,halogen, —CN, —OR_(n8), —OC(O)R_(p8), —OC(O)NR_(q8)R_(r8), —SR_(n8),—S(O)R_(p8), —S(O)₂OH, —S(O)₂R_(p8), —S(O)₂NR_(q8)R_(r8),—NR_(q8)R_(r8), —NR_(n8)COR_(p8), —NR_(n8)CO₂R_(p8),—NR_(n8)CONR_(q8)R_(r8), —NR_(n8)S(O)₂R_(p8), —NR_(n8)S(O)₂OR_(p8),—NR₈S(O)₂ NR_(q8)R_(r8), NO₂, —C(O)R_(n8), —C(O)OR_(n8), and—C(O)NR_(q8)R_(r8), wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of Z⁴ is optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z⁴ or Z^(4d) groups and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of Z⁴ is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z^(4c) groups;

each Z^(4c) is independently selected from of (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n9), —OC(O)R_(p9),—OC(O)NR_(q9)R_(r9), —SR_(n9), —S(O)R_(p9), —S(O)₂OH, —S(O)₂R_(p9),—S(O)₂NR_(q9)R_(r9), —NR_(q9)R_(r9), —NR_(n9)COR_(p9),—NR_(n9)CO₂R_(p9), —NR_(n9)CONR_(q9)R_(r9), —NR_(n9)S(O)₂R_(p9),—NR_(n9)S(O)₂OR_(p9), —NR_(n9)S(O)₂ NR_(q9)R_(r9), NO₂, —C(O)R_(n9),—C(O)OR_(n9), —C(O)NR_(g9)R_(r9), haloaryl, haloheteroaryl,haloheterocycle and (C₁-C₈)heteroalkyl;

each Z^(4d) is independently selected from of (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl and (C₁-C₈)haloalkyl;

each R_(n8) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(n8) is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(4c) or Z^(4d) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl or (C₂-C₈)alkynyl of R_(n8) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(4c) groups;

each R_(p8) is independently selected from (C₁-C₈)alkyl,(C₁-C₆)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle,heterocycle, heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl,heteroaryl and heterocycle of R_(p8) is optionally substituted with oneor more (e.g. 1, 2, 3, 4 or 5) Z^(4c) or Z^(4d) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(p8) is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(4c) groups;

R_(q8) and R_(r8) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(q8) or R_(r8) is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(4c) or Z^(4d) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(q8) or R_(r8) isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(4c)groups, or R_(q8) and R_(r8) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(4c) or Z^(4d) groups;

each R_(n9) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R_(p9) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl, aryl,haloaryl, haloheteroaryl, haloheterocycle, (C₁-C₈)haloalkyl and(C₁-C₈)heteroalkyl; and

R_(q9) and R_(r9) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl; or R_(q9) and R_(r9) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

or a salt thereof.

The invention also provides a pharmaceutical composition comprising acompound of formula I or a pharmaceutically acceptable salt thereof, incombination with a pharmaceutically acceptable carrier.

The invention also provides a method for treating (e.g. preventing,mediating or inhibiting) a Retroviridae viral infection (e.g. an HIVviral infection) in a mammal (e.g. a human), comprising administering acompound of formula I, or a pharmaceutically acceptable salt thereof, tothe mammal.

The invention also provides a method for treating (e.g. preventing,mediating or inhibiting) the proliferation of the HIV virus, treatingAIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g. ahuman), comprising administering a compound of formula I, or apharmaceutically acceptable salt thereof, to the mammal.

The invention also provides a method for treating (e.g. preventing,mediating or inhibiting) an HIV infection in a mammal (e.g. a human),comprising administering a compound of formula I, or a pharmaceuticallyacceptable salt thereof, to the mammal.

The invention also provides a method for treating an HIV infection in amammal (e.g. a human), comprising administering to the mammal in needthereof a therapeutically effective amount of a compound of formula I,or a pharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more additional therapeuticagents selected from the group consisting HIV protease inhibitingcompounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside inhibitors of reverse transcriptase, HIV nucleotideinhibitors of reverse transcriptase, HIV integrase inhibitors, gp41inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsidpolymerization inhibitors, and other drugs for treating HIV, andcombinations thereof.

The invention also provides a compound of formula I, or apharmaceutically acceptable salt thereof for use in medical therapy(e.g. for use in treating (e.g. preventing, mediating or inhibiting) aRetroviridae viral infection (e.g. an HIV viral infection) or theproliferation of the HIV virus or AIDS or delaying the onset of AIDS orARC symptoms in a mammal (e.g. a human)).

The invention also provides a compound of formula I, or apharmaceutically acceptable salt thereof for use in the manufacture of amedicament for treating (e.g. preventing, mediating or inhibiting) aRetroviridae viral infection (e.g. an HIV viral infection) or theproliferation of the HIV virus or AIDS or delaying the onset of AIDS orARC symptoms in a mammal (e.g. a human).

The invention also provides a compound of formula I, or apharmaceutically acceptable salt thereof, for use in the prophylactic ortherapeutic treatment (e.g. prevention, mediation or inhibition) of theproliferation of a Retroviridae virus, an HIV virus or AIDS or for usein the therapeutic treatment of delaying the onset of AIDS or ARCsymptoms.

The invention also provides a compound of formula I, or apharmaceutically acceptable salt thereof, for use in the prophylactic ortherapeutic treatment (e.g. prevention, mediation or inhibition) of aRetroviridae virus infection or an HIV virus infection.

The invention also provides the use of a compound of formula I, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for treating (e.g. preventing, mediating or inhibiting) aRetroviridae virus infection or an HIV virus infection.

The invention also provides processes and intermediates disclosed hereinthat are useful for preparing compounds of formula I or salts thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When trade names are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

“Alkyl” is hydrocarbon containing primary, secondary or tertiary atoms.For example, an alkyl group can have 1 to 20 carbon atoms (i.e,(C₁-C₂₀)alkyl), 1 to 10 carbon atoms (i.e., (C₁-C₁₀)alkyl), 1 to 8carbon atoms (i.e., (C₁-C₈)alkyl) or 1 to 6 carbon atoms (i.e., (C₁-C₆)alkyl). Examples of suitable alkyl groups include, but are not limitedto, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl,—CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu,n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl (—(CH₂)₇CH₃). “Alkyl”also refers to a saturated, branched or straight chain hydrocarbonradical having two monovalent radical centers derived by the removal oftwo hydrogen atoms from the same or two different carbon atoms of aparent alkane. For example, an alkyl group can have 1 to 10 carbon atoms(i.e., (C₁-C₁₀)alkyl), or 1 to 6 carbon atoms (i.e., (C₁-C₆)alkyl) or1-3 carbon atoms (i.e., (C₁-C₃)alkyl). Typical alkyl radicals include,but are not limited to, methylene (—CH₂—), 1,1-ethyl (—CH(CH₃)—),1,2-ethyl (—CH₂CH₂—), 1,1-propyl (—CH(CH₂CH₃)—), 1,2-propyl(—CH₂CH(CH₃)—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—),and the like.

“Alkenyl” is a straight or branched hydrocarbon containing primary,secondary or tertiary carbon atoms with at least one site ofunsaturation, i.e. a carbon-carbon, sp² double bond. For example, analkenyl group can have 2 to 20 carbon atoms (i.e., C₂-C₂₀ alkenyl), 2 to8 carbon atoms (i.e., C₂-C₈ alkenyl), or 2 to 6 carbon atoms (i.e.,C₂-C₆ alkenyl). Examples of suitable alkenyl groups include, but are notlimited to, ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂) and5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is a straight or branched hydrocarbon containing primary,secondary or tertiary carbon atoms with at least one site ofunsaturation, i.e. a carbon-carbon, sp triple bond. For example, analkynyl group can have 2 to 20 carbon atoms (i.e., C₂-C₂₀ alkynyl), 2 to8 carbon atoms (i.e., C₂-C₈ alkynyl), or 2 to 6 carbon atoms (i.e.,C₂-C₆ alkynyl). Examples of suitable alkynyl groups include, but are notlimited to, acetylenic (—C≡CH), propargyl (—CH₂C≡CH), and the like.

The term “halo” or “halogen” as used herein refers to fluoro, chloro,bromo and iodo.

The term “haloalkyl” as used herein refers to an alkyl as definedherein, wherein one or more hydrogen atoms are each replaced by a halosubstituent. For example, a (C₁-C₆)haloalkyl is a (C₁-C₆)alkyl whereinone or more of the hydrogen atoms have been replaced by a halosubstituent. Such a range includes one halo substituent on the alkylgroup to complete halogenation of the alkyl group.

The term “heteroalkyl” as used herein refers to an alkyl as definedherein, wherein one or more of the carbon atoms of the alkyl arereplaced by an O, S, or NR_(q), (or if the carbon atom being replaced isa terminal carbon with an OH, SH or NR_(q2)) wherein each R_(q) isindependently H or (C₁-C₆)alkyl.

The term “aryl” as used herein refers to a single aromatic ring or amultiple condensed ring system. For example, an aryl group can have 6 to20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Arylincludes a phenyl radical. Aryl also includes multiple condensed ringsystems (e.g. ring systems comprising 2, 3 or 4 rings) having about 9 to20 carbon atoms in which at least one ring is aromatic. Such multiplecondensed ring systems may be optionally substituted with one or more(e.g. 1, 2 or 3) oxo groups on any carbocycle portion of the multiplecondensed ring system. It is to be understood that the point ofattachment of a multiple condensed ring system, as defined above, can beat any position of the ring system including an aryl or a carbocycleportion of the ring. Typical aryl groups include, but are not limitedto, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl,and the like.

“Arylalkyl” refers to an alkyl radical as defined herein in which one ofthe hydrogen atoms bonded to a carbon atom is replaced with an arylradical as described herein (i.e., an aryl-alkyl-moiety). The alkylgroup of the “arylalkyl” is typically 1 to 6 carbon atoms (i.e.aryl(C₁-C₆)alkyl). Arylalkyl groups include, but are not limited to,benzyl, 2-phenylethan-1-yl, 1-phenylpropan-1-yl, naphthylmethyl,2-naphthylethan-1-yl and the like.

The term “heteroaryl” as used herein refers to a single aromatic ring ora multiple condensed ring system. The term includes single aromaticrings of from about 1 to 6 carbon atoms and about 1-4 heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur in therings. The sulfur and nitrogen atoms may also be present in an oxidizedform provided the ring is aromatic. Such rings include but are notlimited to pyridyl, pyrimidinyl, oxazolyl or furyl. The term alsoincludes multiple condensed ring systems (e.g. ring systems comprising2, 3 or 4 rings) wherein a heteroaryl group, as defined above, can becondensed with one or more heteroaryls (e.g. naphthyridinyl),heterocycles, (e.g. 1,2,3,4-tetrahydronaphthyridinyl), carbocycles (e.g.5,6,7,8-tetrahydroquinolyl) or aryls (e.g. indazolyl) to form a multiplecondensed ring system. Such multiple condensed ring systems may beoptionally substituted with one or more (e.g. 1, 2, 3 or 4) oxo groupson the carbocycle or heterocycle portions of the condensed ring. It isto be understood that the point of attachment of a multiple condensedring system (as defined above for a heteroaryl) can be at any positionof the multiple condensed ring system including a heteroaryl,heterocycle, aryl or carbocycle portion of the multiple condensed ringsystem and at any suitable atom of the multiple condensed ring systemincluding a carbon atom and heteroatom (e.g. a nitrogen). Exemplaryheteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl,oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl,isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl,quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyland thianaphthenyl.

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated ring or a multiple condensedring system. The term includes single saturated or partially unsaturatedrings (e.g. 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbonatoms and from about 1 to 3 heteroatoms selected from the groupconsisting of oxygen, nitrogen and sulfur in the ring. The ring may besubstituted with one or more (e.g. 1, 2 or 3) oxo groups and the sulfurand nitrogen atoms may also be present in their oxidized forms. Suchrings include but are not limited to azetidinyl, tetrahydrofuranyl orpiperidinyl. The term “heterocycle” also includes multiple condensedring systems (e.g. ring systems comprising 2, 3 or 4 rings) wherein asingle heterocycle ring (as defined above) can be condensed with one ormore heterocycles (e.g. decahydronapthyridinyl), carbocycles (e.g.decahydroquinolyl) or aryls. The rings of a multiple condensed ringsystem can be connected to each other via fused, spiro and bridged bondswhen allowed by valency requirements. It is to be understood that thepoint of attachment of a multiple condensed ring system (as definedabove for a heterocycle) can be at any position of the multiplecondensed ring system including a heterocycle, aryl and carbocycleportion of the ring. It is also to be understood that the point ofattachment for a heterocycle or heterocycle multiple condensed ringsystem can be at any suitable atom of the heterocycle or heterocyclemultiple condensed ring system including a carbon atom and a heteroatom(e.g. a nitrogen). Exemplary heterocycles include, but are not limitedto aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl,dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl,1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl,1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl and1,4-benzodioxanyl.

“Heteroarylalkyl” refers to an alkyl radical as defined herein in whichone of the hydrogen atoms bonded to a carbon atom is replaced with aheteroaryl radical as described herein (i.e., aheteroaryl-alkyl-moiety). The alkyl group of the “heteroarylalkyl” istypically 1 to 6 carbon atoms (i.e. heteroaryl(C₁-C₆)alkyl).Heteroarylalkyl groups include, but are not limited to heteroaryl-CH₂—,heteroaryl-CH(CH₃)—, heteroaryl-CH₂CH₂—, 2-(heteroaryl)ethan-1-yl, andthe like, wherein the “heteroaryl” portion includes any of theheteroaryl groups described above. One skilled in the art will alsounderstand that the heteroaryl group can be attached to the alkylportion of the heteroarylalkyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. Examples of heteroarylalkyls include by way ofexample and not limitation 5-membered sulfur, oxygen, and/or nitrogencontaining heteroaryls such as thiazolylmethyl, 2-thiazolylethan-1-yl,imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-memberedsulfur, oxygen, and/or nitrogen containing heteroaryls suchpyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.

“Heterocyclylalkyl” refers to an alkyl radical as defined herein inwhich one of the hydrogen atoms bonded to a carbon atom is replaced witha heterocyclyl radical as described herein (i.e., aheterocyclyl-alkyl-moiety). The alkyl group of the “heterocyclylalkyl”is typically 1 to 6 carbon atoms (i.e. heterocyclyl(C₁-C₆)alkyl).Typical heterocyclylalkyl groups include, but are not limited toheterocyclyl-CH₂—, heterocyclyl-CH(CH₃)—, heterocyclyl-CH₂CH₂—,2-(heterocyclyl)ethan-1-yl, and the like, wherein the “heterocyclyl”portion includes any of the heterocyclyl groups described above. Oneskilled in the art will also understand that the heterocyclyl group canbe attached to the alkyl portion of the heterocyclyl alkyl by means of acarbon-carbon bond or a carbon-heteroatom bond, with the proviso thatthe resulting group is chemically stable. Examples of heterocyclylalkylsinclude by way of example and not limitation 5-membered sulfur, oxygen,and/or nitrogen containing heterocycles such as tetrahydrofuranylmethyland pyrroldinylmethyl, etc., and 6-membered sulfur, oxygen, and/ornitrogen containing heterocycles such as piperidinylmethyl,piperazinylmethyl, morpholinylmethyl, etc.

The term “carbocycle” or “carbocyclyl” refers to a single saturated(i.e., cycloalkyl) or a single partially unsaturated (e.g.,cycloalkenyl, cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms(i.e. (C₃-C₇)carbocycle). The term “carbocycle” or “carbocyclyl” alsoincludes multiple condensed ring systems (e.g. ring systems comprising2, 3 or 4 carbocyclic rings). Accordingly, carbocycle includesmulticyclic carbocyles having 6 to 12 carbon atoms as a bicycle (e.g.bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane), and up to about 20 carbonatoms as a polycycle.

Multicyclic carbocyles can be connected to each other via a singlecarbon atom to form a spiro connection (e.g. spiropentane,spiro[4,5]decane, spiro[4.5]decane, etc), via two adjacent carbon atomsto form a fused connection such as a bicyclo [4,5], [5,5], [5,6] or[6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6]system (e.g. decahydronaphthalene, norsabinane, norcarane) or via twonon-adjacent carbon atoms to form a bridged connection (e.g. norbornane,bicyclo[2.2.2]octane, etc). The “carbocycle” or “carbocyclyl” can alsobe optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups.Non-limiting examples of monocyclic carbocycles include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and1-cyclohex-3-enyl.

“Carbocyclylalkyl” refers to an alkyl radical as defined herein in whichone of the hydrogen atoms bonded to a carbon atom is replaced with acarbocyclyl radical as described herein (i.e., acarbocyclyl-alkyl-moiety). The alkyl group of the “carbocyclylalkyl” istypically 1 to 6 carbon atoms (i.e. carbocyclyl(C₁-C₆)alkyl). Typicalcarbocyclyl alkyl groups include, but are not limited tocarbocyclyl-CH₂—, carbocyclyl-CH(CH₃)—, carbocyclyl-CH₂CH₂—,2-(carbocyclyl)ethan-1-yl, and the like, wherein the “carbocyclyl”portion includes any of the carbocyclyl groups described above.

The term “haloaryl” as used herein refers to an aryl as defined herein,wherein one or more hydrogen atoms of the aryl are each replacedindependently by a halo substituent. Such a range includes one halosubstituent on the aryl group to complete halogenation of the arylgroup.

The term “haloheteroaryl” as used herein refers to a heteroaryl asdefined herein, wherein one or more hydrogen atoms of the heteroaryl areeach replaced independently by a halo substituent. Such a range includesone halo substituent on the heteroaryl group to complete halogenation ofthe heteroaryl group.

The term “haloheterocycle” as used herein refers to a heterocycle asdefined herein, wherein one or more hydrogen atoms of the heterocycleare each replaced independently by a halo substituent. Such a rangeincludes one halo substituent on the heterocycle group to completehalogenation of the heterocycle group.

One skilled in the art will recognize that substituents and othermoieties of the compounds of formula I should be selected in order toprovide a compound which is sufficiently stable to provide apharmaceutically useful compound which can be formulated into anacceptably stable pharmaceutical composition. Compounds of formula Iwhich have such stability are contemplated as falling within the scopeof the present invention.

The modifier “about” used in connection with a quantity is inclusive ofthe stated value and has the meaning dictated by the context (e.g.,includes the degree of error associated with measurement of theparticular quantity).

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers or axesof chirality and whose molecules are not mirror images of one another.Diastereomers typically have different physical properties, e.g.,melting points, boiling points, spectral properties, and reactivities.Mixtures of diastereomers may separate under high resolution analyticalprocedures such as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

It is to be understood that certain variables of formula I may havealternative orientations. For example, the —OCR^(3a)R^(3b)— variable forW may be oriented in a manner in which the CR^(3a)R^(3b) group isconnected to the carbonyl of formula I and the O is connected to the R¹group of formula I and also in a manner in which the CR^(3a)R^(3b) groupis connected to the R¹ group of formula I and the O is connected to thecarbonyl of formula I. In one embodiment of the invention theCR^(3a)R^(3b) group is connected to the carbonyl of formula I and the Ois connected to the R¹ group of formula I. In another embodiment of theinvention the CR^(3a)R^(3b) group is connected to the R¹ group offormula I and the O is connected to the carbonyl of formula I.

The term “treatment” or “treating,” to the extent it relates to adisease or condition includes preventing the disease or condition fromoccurring, inhibiting the disease or condition, eliminating the diseaseor condition, and/or relieving one or more symptoms of the disease orcondition.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes (D and L) or (Rand S) are used to denote the absolute configuration of the moleculeabout its chiral center(s). The prefixes d and l or (+) and (−) areemployed to designate the sign of rotation of plane-polarized light bythe compound, with (−) or l meaning that the compound is levorotatory. Acompound prefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer may also be referred toas an enantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity.

Protecting Groups

In the context of the present invention, protecting groups includeprodrug moieties and chemical protecting groups.

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive.

Protected compounds may also exhibit altered, and in some cases,optimized properties in vitro and in vivo, such as passage throughcellular membranes and resistance to enzymatic degradation orsequestration. In this role, protected compounds with intendedtherapeutic effects may be referred to as prodrugs. Another function ofa protecting group is to convert the parental drug into a prodrug,whereby the parental drug is released upon conversion of the prodrug invivo. Because active prodrugs may be absorbed more effectively than theparental drug, prodrugs may possess greater potency in vivo than theparental drug. Protecting groups are removed either in vitro, in theinstance of chemical intermediates, or in vivo, in the case of prodrugs.With chemical intermediates, it is not particularly important that theresulting products after deprotection, e.g., alcohols, bephysiologically acceptable, although in general it is more desirable ifthe products are pharmacologically innocuous.

Protecting groups are available, commonly known and used, and areoptionally used to prevent side reactions with the protected groupduring synthetic procedures, i.e. routes or methods to prepare thecompounds of the invention. For the most part the decision as to whichgroups to protect, when to do so, and the nature of the chemicalprotecting group “PG” will be dependent upon the chemistry of thereaction to be protected against (e.g., acidic, basic, oxidative,reductive or other conditions) and the intended direction of thesynthesis. PGs do not need to be, and generally are not, the same if thecompound is substituted with multiple PG. In general, PG will be used toprotect functional groups such as carboxyl, hydroxyl, thio, or aminogroups and to thus prevent side reactions or to otherwise facilitate thesynthetic efficiency. The order of deprotection to yield freedeprotected groups is dependent upon the intended direction of thesynthesis and the reaction conditions to be encountered, and may occurin any order as determined by the artisan.

Various functional groups of the compounds of the invention may beprotected. For example, protecting groups for —OH groups (whetherhydroxyl, carboxylic acid, phosphonic acid, or other functions) include“ether- or ester-forming groups”. Ether- or ester-forming groups arecapable of functioning as chemical protecting groups in the syntheticschemes set forth herein. However, some hydroxyl and thio protectinggroups are neither ether- nor ester-forming groups, as will beunderstood by those skilled in the art, and are included with amides,discussed below.

A very large number of hydroxyl protecting groups and amide-forminggroups and corresponding chemical cleavage reactions are described inProtective Groups in Organic Synthesis, Theodora W. Greene (John Wiley &Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (“Greene”). See alsoKocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart,New York, 1994), which is incorporated by reference in its entiretyherein. In particular Chapter 1, Protecting Groups: An Overview, pages1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3,Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl ProtectingGroups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages155-184. For protecting groups for carboxylic acid, phosphonic acid,phosphonate, sulfonic acid and other protecting groups for acids seeGreene as set forth below.

Stereoisomers

The compounds of the invention may have chiral centers, e.g., chiralcarbon or phosphorus atoms. The compounds of the invention thus includeracemic mixtures of all stereoisomers, including enantiomers,diastereomers, and atropisomers. In addition, the compounds of theinvention include enriched or resolved optical isomers at any or allasymmetric, chiral atoms. In other words, the chiral centers apparentfrom the depictions are provided as the chiral isomers or racemicmixtures. Both racemic and diastereomeric mixtures, as well as theindividual optical isomers isolated or synthesized, substantially freeof their enantiomeric or diastereomeric partners, are all within thescope of the invention. The racemic mixtures can be separated into theirindividual, substantially optically pure isomers through well-knowntechniques such as, for example, the separation of diastereomeric saltsformed with optically active adjuncts, e.g., acids or bases followed byconversion back to the optically active substances. In most instances,the desired optical isomer is synthesized by means of stereospecificreactions, beginning with the appropriate stereoisomer of the desiredstarting material.

It is to be understood that for compounds of the invention when a bondis drawn in a non-stereochemical manner (e.g. flat) the atom to whichthe bond is attached includes all stereochemical possibilities. It isalso to be understood that when a bond is drawn in a stereochemicalmanner (e.g. bold, bold-wedge, dashed or dashed-wedge) the atom to whichthe stereochemical bond is attached has the stereochemistry as shownunless otherwise noted.

Accordingly, in one embodiment, a compound of the invention may begreater than 50% a single enantiomer. In another embodiment, a compoundof the invention may be at least 51% a single enantiomer. In anotherembodiment, a compound of the invention may be at least 60% a singleenantiomer. In another embodiment, a compound of the invention may be atleast 70% a single enantiomer. In another embodiment, a compound of theinvention may be at least 80% a single enantiomer. In anotherembodiment, a compound of the invention may be at least 90% a singleenantiomer. In another embodiment, a compound of the invention may be atleast 95% a single enantiomer. In another embodiment, a compound of theinvention may be at least 98% a single enantiomer. In anotherembodiment, a compound of the invention may be at least 99% a singleenantiomer. In another embodiment, a compound of the invention may begreater than 50% a single diasteromer. In another embodiment, a compoundof the invention may be at least 51% a single diasteromer. In anotherembodiment, a compound of the invention may be at least 60% a singlediastereomer. In another embodiment, a compound of the invention may beat least 70% a single diastereomer. In another embodiment, a compound ofthe invention may be at least 80% a single diastereomer. In anotherembodiment, a compound of the invention may be at least 90% a singlediastereomer. In another embodiment, the compounds of the invention areat least 95% a single diastereomer. In another embodiment, a compound ofthe invention may be at least 98% a single diastereomer. In anotherembodiment, a compound of the invention may be at least 99% a singlediastereomer.

The compounds of the invention can also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.Other examples include keto-enol tautomers of hydroxy heterocycles suchas hydroxy quinolines (e.g. 2-hydroxy quinoline and quinolin-2-ones).

Salts and Hydrates

Examples of pharmaceutically acceptable salts of the compounds of theinvention include salts derived from an appropriate base, such as analkali metal (for example, sodium), an alkaline earth metal (forexample, magnesium), ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl).Pharmaceutically acceptable salts of a hydrogen atom or an amino groupinclude for example salts of organic carboxylic acids such as acetic,benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic,lactobionic and succinic acids; organic sulfonic acids, such asmethanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonicacids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric,phosphoric and sulfamic acids. Pharmaceutically acceptable salts of acompound of a hydroxy group include the anion of said compound incombination with a suitable cation such as Na⁺ and NX₄ ⁺ (wherein X isindependently selected from H or a C₁-C₄ alkyl group).

For therapeutic use, salts of active ingredients of the compounds of theinvention will typically be pharmaceutically acceptable, i.e. they willbe salts derived from a physiologically acceptable acid or base.However, salts of acids or bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a compound of formula I or another compound of theinvention. All salts, whether or not derived from a physiologicallyacceptable acid or base, are within the scope of the present invention.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, typically amines, or to acidic groups. Finally,it is to be understood that the compositions herein comprise compoundsof the invention in their un-ionized, as well as zwitterionic form, andcombinations with stoichiometric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of theparental compounds with one or more amino acids. Any of the natural orunnatural amino acids are suitable, especially the naturally-occurringamino acids found as protein components, although the amino acidtypically is one bearing a side chain with a basic or acidic group,e.g., lysine, arginine or glutamic acid, or a neutral group such asglycine, serine, threonine, alanine, isoleucine, or leucine.

Specific values listed below for radicals, substituents, and ranges inthe embodiments of the invention are for illustration only; they do notexclude other defined values or other values within defined ranges forthe radicals and substituents.

Isotopes

It is understood by one skilled in the art that this invention alsoincludes any compound claimed that may be enriched at any or all atomsabove naturally occurring isotopic ratios with one or more isotopes suchas, but not limited to, deuterium (²H or D). As a non-limiting example,a —CH₃ group may be substituted with —CD₃.

Compounds of Formula I.

A specific group of compounds of formula I are compounds of formula I′:

or a salt thereof.

A specific group of compounds of formula I are compounds of formula Ia:

or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Ia′:

or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Ib:

or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Ic:

or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Ic′:

or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Id:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Ie:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Ie′:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Ibb:

or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Icc:

or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Icc′:

or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Idd:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Iee:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Iee′:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula If:

or a salt thereof.

Another specific group of compounds of formula I are compounds offormula If′:

or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Ig:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Ih.

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Ii:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Ij:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Ij′:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Ik:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Im:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula Im′:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula In, Io, Io′, Ip, Iq, Iq′, Ir, Is or Is′:

wherein each Z^(2a) is independently H or Z², or a salt thereof.

Another specific group of compounds of formula I are compounds offormula It:

or a salt thereof.

Another specific group of compounds of formula I are compounds offormula It′:

or a salt thereof.

Specific values listed herein below are values for compounds of formulaI as well as compounds of sub-formulas of formula I (e.g. formulas I′Ia, Ia′, Ib, Ic, Ic′, Id, Ie, Ie′, Ibb, Icc, Icc′, Idd, Iee, Iee, If,If′, Ig, Ih Ii, Ij, Ij′, Ik, Im, Im′, In, Io, Io′, Ip, Iq, Iq′, Ir, Is,Is′, It and It′) A specific value for W is CR^(3a)R^(3b) or NR⁴.

Another specific value for W is —CR^(3a)R^(3b)—, —O—, —NR⁴— or—OCR^(3a)R^(3b)—.

Another specific value for W is —CR^(3a)R^(3b)—, —OCR^(3a)R^(3b)— orabsent.

Another specific value for W is —CR^(3a)R^(3b)—.

A specific group of compounds of formula I are compounds wherein R⁴ is Hand, wherein each R^(3a) and R^(3b) is independently selected from H,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, NR_(a)R_(b), and —NR_(c)COR_(d), orR^(3a) and R^(3b) together with the carbon to which they are attachedform a (C₃-C₆)carbocycle.

Another specific value for W is —CH₂—, —CH(CH₃)—, —CH(CH₂CH₃)—,—CH(CF₃)—, —CH(CH₂CF₃)—, —CH(CH₂CHF₂)—, —CH(NH₂)—, —CH(NHC(═O)CH₃)—,1,1-cyclopropyldiyl or —NH—.

Another specific value for W is —CH₂—, —CH(CH₃)—, —CH(NH₃)—,—CH(NHC(═O)CH₃)—, 1,1-cyclopropyldiyl or —NH—.

Another specific value for W is —CH₂—.

A specific group of compounds of formula I are compounds wherein B isabsent.

A specific value for R² is a 6-membered aryl wherein the 6-membered arylis optionally substituted with one or more (e.g. 1, 2 or 3) Z⁴ groups.

A specific value for Z⁴ is (C₃-C₇)carbocycle, halogen or —CN.

Another specific value for Z⁴ is cyclopropyl, fluoro or —CN.

Another specific value for Z⁴ is fluoro.

Another specific value for Z⁴ is fluoro or chloro.

Another specific value for Z⁴ is (C₁-C₈)alkyl, (C₃-C₇)carbocycle,halogen or OR_(n6), wherein any (C₁-C₈)alkyl of Z⁴ is optionallysubstituted with one or more halogens.

Another specific value for Z⁴ is (C₃-C₇)carbocycle, halogen, methyl or—CN.

Another specific value for Z⁴ is halogen.

Another specific value for R² is:

Another specific value for R² is:

Another specific value for R² is:

Another specific value for R² is:

A specific value for R¹ is heteroaryl or heterocycle, wherein anyheteroaryl or heterocycle of R¹ is optionally substituted with one ormore Z³ groups.

Another specific value for R¹ is bicyclic-heteroaryl,tricyclic-heteroaryl, bicyclic-heterocycle or tricyclic-heterocycle,wherein any bicyclic-heteroaryl, tricyclic-heteroaryl,bicyclic-heterocycle or tricyclic-heterocycle, of R¹ is optionallysubstituted with one or more Z³ groups.

Another specific value for R¹ is 4,5,6,7-tetrahydroindazolyl,5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridinyl,1,4,5,7-tetrahydropyranopyrazolyl,3-oxo-2,3,4,5,6,7-hexahydro-indazolyl, pyrrolo[2,3-c]pyridinyl,pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl,1H-pyrrolo[3,2-b]pyridinyl, benzoimidazolyl, 5-phenyl-pyrazolyl,pyrrolo[3,2-d]pyrimidinyl, 5-oxo-5,6-dihydro-1H-pyrrolo[2,3-c]pyridinyl,6-oxo-6,7-dihydro-1H-pyrrolo[2,3-b]pyridinyl,1,7-dihydropyrrolo[3,2-f]indazolyl, 1,6-dihydropyrrolo[2,3-e]indazolyl,2-oxo-2H-thiazolo[5,4-f]indoly, 2-oxoindolin-3-yl or indolyl, whereinany 4,5,6,7-tetrahydroindazolyl,5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridinyl,1,4,5,7-tetrahydropyranopyrazolyl,3-oxo-2,3,4,5,6,7-hexahydro-indazolyl, pyrrolo[2,3-c]pyridinyl,pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl,1H-pyrrolo[3,2-b]pyridinyl, benzoimidazolyl, 5-phenyl-pyrazolyl,pyrrolo[3,2-d]pyrimidinyl, 5-oxo-5,6-dihydro-1H-pyrrolo[2,3-c]pyridinyl,6-oxo-6,7-dihydro-1H-pyrrolo[2,3-b]pyridinyl,1,7-dihydropyrrolo[3,2-f]indazolyl, 1,6-dihydropyrrolo[2,3-e]indazolyl,2-oxo-2H-thiazolo[5,4-f]indolyl, 2-oxoindolin-3-yl or indolyl of R¹ isoptionally substituted with one or more Z³ groups.

Another specific value for R¹ is 4,5,6,7-tetrahydroindazolyl or indolyl,wherein any 4,5,6,7-tetrahydroindazolyl or indolyl of R¹ is optionallysubstituted with one or more Z³ groups.

Another specific value for R¹ is 4,5,6,7-tetrahydroindazolyl,5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridinyl or indolyl, wherein any4,5,6,7-tetrahydroindazolyl,5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridinyl or indolyl of R¹ isoptionally substituted with one or more Z³ groups.

Another specific value for R¹ is tricyclic-heteroaryl ortricyclic-heterocycle, wherein any tricyclic-heteroaryl ortricyclic-heterocycle of R¹ is optionally substituted with one or moreZ³ groups.

Another specific value for R¹ is bicyclic-heteroaryl,tricyclic-heteroaryl, bicyclic-heterocycle or tricyclic-heterocycle,wherein any bicyclic-heteroaryl, tricyclic-heteroaryl,bicyclic-heterocycle or tricyclic-heterocycle of R¹ contains at leastone partially unsaturated ring, and wherein any bicyclic-heteroaryl,tricyclic-heteroaryl, bicyclic-heterocycle or tricyclic-heterocycle ofR¹ is optionally substituted with one or more Z³ groups.

Another specific value for R¹ is tricyclic-heteroaryl ortricyclic-heterocycle, wherein any tricyclic-heteroaryl ortricyclic-heterocycle of R¹ contains one aromatic ring, one partiallyunsaturated ring, and one fully saturated ring, and wherein anytricyclic-heteroaryl or tricyclic-heterocycle of R¹ is optionallysubstituted with one or more Z³ groups.

Another specific value for R¹ is bicyclic-heteroaryl,tricyclic-heteroaryl, bicyclic-heterocycle or tricyclic-heterocycle,wherein any bicyclic-heteroaryl, tricyclic-heteroaryl,bicyclic-heterocycle or tricyclic-heterocycle of R¹ contains 5 or morehalogen atoms, and wherein any bicyclic-heteroaryl,tricyclic-heteroaryl, bicyclic-heterocycle or tricyclic-heterocycle ofR¹ is optionally additionally substituted with one or more Z³ groups.

Another specific value for R¹ is tricyclic-heteroaryl ortricyclic-heterocycle, wherein any tricyclic-heteroaryl ortricyclic-heterocycle of R¹ contains a bridged bicyclic carbocycle or abridged bicyclic heterocycle, and wherein any tricyclic-heteroaryl ortricyclic-heterocycle of R¹ is optionally substituted with one or moreZ³ groups.

Another specific value for R¹ is tricyclic-heteroaryl ortricyclic-heterocycle, wherein any tricyclic-heteroaryl ortricyclic-heterocycle of R contains a spiro-connected bicycliccarbocycle or a spiro-connected bicyclic heterocycle, and wherein anytricyclic-heteroaryl or tricyclic-heterocycle of R¹ is optionallysubstituted with one or more Z³ groups.

Another specific value for R¹ is:

wherein Z^(3e), Z^(3f), and Z^(3g) are each independently selected fromH and Z³; or Z^(3e) is H or Z³, and Z^(3f) and Z^(3g) together with thecarbons to which they are attached form a 5, 6, or 7-memberedheterocycle or a 5, 6, or 7-membered carbocycle, which 5, 6, or7-membered heterocycle or a 5, 6, or 7-membered carbocycle is optionallysubstituted with one or more Z³ groups.

Another specific value for R¹ is:

wherein Z^(3e) is H or Z³, and Z^(3f) and Z^(3g) together with thecarbons to which they are attached form a 5, 6, or 7-memberedheterocycle or a 5, 6, or 7-membered carbocycle, which 5, 6, or7-membered heterocycle or a 5, 6, or 7-membered carbocycle is optionallysubstituted with one or more Z³ groups.

Another specific value for R¹ is heteroaryl or heterocycle, wherein anyheteroaryl or heterocycle of R¹ is optionally substituted with one ormore Z³ groups, provided R¹ does not include indolyl.

Another specific value for R¹ is bicyclic-heteroaryl,tricyclic-heteroaryl, bicyclic-heterocycle or tricyclic-heterocycle,wherein any bicyclic-heteroaryl, tricyclic-heteroaryl,bicyclic-heterocycle or tricyclic-heterocycle, of R¹ is optionallysubstituted with one or more Z³ groups, provided R¹ does not includeindolyl.

Another specific value for R¹ is bicyclic-heteroaryl,tricyclic-heteroaryl, bicyclic-heterocycle or tricyclic-heterocycle,wherein any bicyclic-heteroaryl, tricyclic-heteroaryl,bicyclic-heterocycle or tricyclic-heterocycle of R¹ contains 5 or morehalogen atoms, and wherein any bicyclic-heteroaryl,tricyclic-heteroaryl, bicyclic-heterocycle or tricyclic-heterocycle ofR¹ is optionally additionally substituted with one or more Z³ groups,provided R¹ does not include indolyl.

Another specific value for R¹ is aryl, heteroaryl or heterocycle,wherein any aryl, heteroaryl or heterocycle of R¹ is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z³ groups, providedR¹ does not include indolyl.

A specific value for Z³ is (C₁-C₈)alkyl, halogen, —OR_(n4),—NR_(q4)R_(r4) or —NR_(n4)S(O)₂R_(p4), wherein any (C₁-C₈)alkyl of Z³ isoptionally substituted with one or more Z^(3a) groups.

Another specific value for Z³ is (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, aryl, halogen, —CN, —OR_(n4),—S(O)₂R_(p4), —NR_(n4)CO₂R_(p4), —NR_(n4)S(O)₂R_(p4), —C(O)R_(n4),—C(O)OR_(n4), —C(O)NR_(q4)R_(r4) or —B(OR_(q4))(OR_(r4)), wherein any(C₃-C₇)carbocycle and aryl of Z³ is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(3a) or Z^(3b) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of Z³ is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(3a) groups.

Another specific value for Z³ is (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, aryl, halogen, —CN, —OR_(n4),—S(O)₂R_(p4), —NR_(n4)S(O)₂R_(p4), —S(O)₂NR_(q4)R_(r4), —NR_(q4)R_(r4),—C(O)R_(n4), —C(O)NR_(q4)R_(r4) or —NR_(n4)COR_(q4) wherein any(C₃-C₇)carbocycle and aryl of Z³ is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(3a) or Z^(3b) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of Z³ is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(3a) groups

Another specific value for Z³ is methyl, trifluoromethyl, hydroxy,methoxy, benzyloxy, fluoro, —NHSO₂CH₃, 2-hydroxyprop-2yl, difluoromethylor amino.

A specific value for Z^(3a) is halogen.

Another specific value for Z^(3a) is halogen and —OR_(n5).

Another specific value for Z^(3a) is, aryl, heterocycle, halogen,—OR_(n5), —NR_(q5)R_(r5) or —NR_(5n)CO₂R_(p5), wherein any aryl,heteroaryl and heterocycle of Z^(3a) is optionally substituted with oneor more (e.g. 1, 2, 3, 4 or 5) Z^(3c) or Z^(3d) groups.

Another specific value for Z³ is methyl, trifluoromethyl, hydroxy,methoxy, benzyloxy, fluoro, —NHSO₂CH₃, 2-hydroxyprop-2yl, difluoromethylor amino.

Another specific value for Z³ is methyl, trifluoromethyl, hydroxy,methoxy, benzyloxy, fluoro or —NHSO₂CH₃.

A specific value for R¹ is:

Another specific value for R¹ is:

Another specific value for R¹ is:

Another specific value for R¹ is:

Another specific value for R¹ is:

Another specific value for R¹ is:

A specific value for A is pyridinyl, pyrimidinyl, pyrazinyl orpyridazinyl, wherein any pyridinyl, pyrimidinyl, pyrazinyl, orpyridazinyl of A is substituted with one Z¹ group and optionallysubstituted with one or more Z² groups.

Another specific value for A is:

wherein each Z^(2a) is independently selected from H and Z².

Another specific value for A is:

wherein each Z^(2a) is independently selected from H and Z².

Another specific value for A is:

wherein each Z^(2a) is independently selected from H and Z².

A specific value for Z^(2a) is H.

A specific value for Z¹ is (C₂—C)alkynyl, (C₃-C₇)carbocycle, aryl,heteroaryl or heterocycle, wherein any (C₃-C₇)carbocycle, aryl,heteroaryl or heterocycle of Z¹ is optionally substituted with one ormore Z^(1a) or Z^(1b) groups and wherein any (C₂-C₈)alkynyl of Z¹ isoptionally substituted with one or more Z^(1a) groups.

Another specific value for Z¹ is ethynyl, cyclohexyl, phenyl, pyridyl,thiophenyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, indazolyl orisoindolin-1-one, wherein any cyclohexyl, phenyl, pyridyl, thiophenyl,isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, indazolyl orisoindolin-1-one of Z¹ is optionally substituted with one or more Z^(1a)or Z^(1b) groups, and wherein any ethynyl of Z¹ is optionallysubstituted with one or more Z^(1a) groups.

Another specific value for Z¹ is (C₂-C₈)alkynyl or aryl, wherein anyaryl of Z¹ is optionally substituted with one or more Z^(1a) or Z^(1b)groups and wherein any (C₂-C₈)alkynyl of Z¹ is optionally substitutedwith one or more Z^(1a) groups.

Another specific value for Z¹ is ethynyl or phenyl, wherein any phenylof Z¹ is optionally substituted with one or more Z^(1a) or Z^(1b)groups, and wherein any ethynyl of Z¹ is optionally substituted with oneor more Z^(1a) groups.

Another specific value for Z¹ is (C₂-C₈)alkynyl, (C₃-C₇)carbocycle,aryl, heteroaryl or heterocycle, wherein any (C₃-C₇)carbocycle, aryl,heteroaryl, or heterocycle of Z¹ is optionally substituted with one ormore Z^(1a) or Z^(1b) groups and wherein any (C₂-C₈)alkynyl of Z¹ isoptionally substituted with one or more Z^(1a) groups.

Another specific value for Z¹ is (C₂-C₈)alkynyl, aryl, heteroaryl orheterocycle, wherein any aryl, heteroaryl, or heterocycle of Z¹ isoptionally substituted with one or more Z^(1a) or Z^(1b) groups andwherein any (C₂-C₈)alkynyl of Z¹ is optionally substituted with one ormore Z a groups.

Another specific value for Z¹ is aryl, heteroaryl or heterocycle,wherein any aryl, heteroaryl, or heterocycle of Z¹ is optionallysubstituted with one or more Z^(1a) or Z^(1b) groups.

A specific value for Z^(1a) is (C₃-C₇)carbocycle, heteroaryl,heterocycle, halogen, —CN, —OR_(n2), —S(O)₂NR_(q2)R_(r2),—NR_(q2)R_(r2), —C(O)R_(n2), —C(O)NR_(p2)R_(q2) or —C(═NOR_(n2))CN,wherein any (C₃-C₇)carbocycle, heteroaryl or heterocycle of Z^(1a) isoptionally substituted with one or more Z^(1c) or Z^(1d) groups, andeach Z^(1b) is independently selected from (C₁-C₈)alkyl, wherein any(C₁-C₈)alkyl of Z^(b) is optionally substituted with one or more Z^(1c)groups.

Another specific value for Z^(1a) is cyclopropyl,N-ethyl-3-amine-oxetan-3-yl, N-ethyl-1 amine-2,2,2-trifluoroethanyl,triazol-1-yl, tetrazol-5-yl, 3-trifluoromethylisoxazol-5-yl,2-carboxy-ethyl, 2-morpholinoethoxy, fluoro, chloro, —CN, methoxy,—S(O)₂NH₂, —C(═NOCH₃)CN, —C(O)NH₂, —C(O)N(CH₃)₂ or —C(O)NH(CH₃), andwherein each Z^(1b) is methyl.

Another specific value for Z^(1a) is aryl, heteroaryl, heterocycle,(C₃-C₇)carbocycle, halogen, CN, —OR_(n2), —S(O)₂R_(p2),—S(O)₂NR_(q2)R_(r2), —NR_(q2)R_(r2), —NR_(n2)COR_(p2),—NR_(n2)CO₂R_(p2), —NR_(n2)CONR_(q2)R_(r2), —NR_(n2)S(O)₂R_(p2), —C(O)R₂and —C(O)NR_(q2)R_(r2), wherein any aryl, heteroaryl, heterocycle and(C₃-C₇)carbocycle of Z^(1a) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups; and each Z^(1b) isindependently selected from (C₁-C₈)alkyl and (C₂-C₈)alkynyl, wherein any(C₁-C₈)alkyl and (C₂-C₈)alkynyl of Z^(1b) is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z^(1c) groups.

Another specific value for Z^(1a) is aryl, heteroaryl, heterocycle,halogen, CN, —OR_(n2), —S(O)₂R_(p2), —S(O)₂NR_(q2)R_(r2),—NR_(q2)R_(r2), —NR_(n2)COR_(p2), —NR_(n2)CO₂R_(p2),—NR_(n2)CONR_(q2)R_(r2), —NR_(n2)S(O)₂R_(p2), —C(O)R_(n2) and—C(O)NR_(q2)R_(r2), wherein any aryl, heteroaryl, heterocycle and(C₃-C₇)carbocycle of Z^(1a) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups; and each Z^(1b) isindependently selected from (C₁-C₈)alkyl and (C₂-C₈)alkynyl, wherein any(C₁-C₈)alkyl and (C₂-C₈)alkynyl of Z^(1b) is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z^(1c) groups.

A specific value for Z¹ is:

Another value for Z¹ is:

A specific value for A is:

Another specific value for A is:

A specific value for R¹ is a value for R¹ as depicted in any or all ofthe examples as described herein below.

A specific value for R² is a value for R² as depicted in any or all ofthe examples as described herein below.

A specific value for W is a value for W as depicted in any or all of theexamples as described herein below.

A specific value for A is a value for A as depicted in any or all of theexamples as described herein below.

In one embodiment a compound of the invention is a compound of formula Ias described in any or all of the examples as described herein below.

In one embodiment a compound of the invention is an isomer (e.g.stereoisomer such as an enantiomer or diastereomer) of a compound offormula I as described in any or all of the examples as described hereinbelow.

In one embodiment a compound of the invention is a racemic mixture of acompound of formula I as described in any or all of the examples asdescribed herein below.

In one embodiment a heteroaryl (multiple condensed ring system) is aring system comprising 2, 3 or 4 rings.

In one embodiment a heteroaryl (multiple condensed ring system) is aring system comprising 3 or 4 rings.

In one embodiment a heteroaryl (multiple condensed ring system) is aring system comprising 2 or 3 rings.

In one embodiment a heteroaryl (multiple condensed ring system) is aring system comprising 2 rings.

In one embodiment a heteroaryl (multiple condensed ring system) is aring system comprising 3 rings.

In one embodiment a heteroaryl (multiple condensed ring system) is aring system comprising 4 rings.

In one embodiment a heterocycle (multiple condensed ring system) is aring system comprising 2, 3 or 4 rings.

In one embodiment a heterocycle (multiple condensed ring system) is aring system comprising 3 or 4 rings.

In one embodiment a heterocycle (multiple condensed ring system) is aring system comprising 2 or 3 rings.

In one embodiment a heterocycle (multiple condensed ring system) is aring system comprising 2 rings.

In one embodiment a heterocycle (multiple condensed ring system) is aring system comprising 3 rings.

In one embodiment a heterocycle (multiple condensed ring system) is aring system comprising 4 rings.

In one embodiment the term “carbocycle” or “carbocyclyl” refers to asingle saturated (i.e., cycloalkyl) or a single partially unsaturated(e.g., cycloalkenyl, cycloalkadienyl, etc.) ring having 3 to 7 carbonatoms (i.e. (C₃-C₇)carbocycle). The term “carbocycle” or “carbocyclyl”also includes multiple condensed ring systems (e.g. ring systemscomprising 2, 3 or 4 carbocyclic rings). Accordingly, carbocycleincludes multicyclic carbocyles having 7 to 12 carbon atoms as abicycle, and up to about 20 carbon atoms as a polycycle. Multicycliccarbocyles can be connected to each other via a single carbon atom toform a spiro connection (e.g. spiropentane, spiro[4,5]decane,spiro[4.5]decane, etc), via two adjacent carbon atoms to form a fusedconnection such as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system (e.g.decahydronaphthalene, norsabinane, norcarane) or via two non-adjacentcarbon atoms to form a bridged connection (e.g. norbornane,bicyclo[2.2.2]octane, etc). The “carbocycle” or “carbocyclyl” can alsobe optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups.Non-limiting examples of monocyclic carbocycles include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and1-cyclohex-3-enyl.

In one embodiment the compounds of formula I do not include thecompound:

In one embodiment the compounds of formula I include:

and salts thereof.

In one embodiment the compounds of formula I include:

and salts thereof.

In one embodiment, the invention provides a compound of the inventionwhich is a compound of formula I′:

wherein:

A is a 6-membered heteroaryl comprising one or two nitrogens, whereinthe 6-membered heteroaryl is substituted with one Z¹ group andoptionally substituted with one or more (e.g. 1, 2, or 3) Z² groups;

W is CR^(3a)R^(3b), O or NR⁴;

R¹ is aryl, heteroaryl or heterocycle, wherein any aryl, heteroaryl orheterocycle of R¹ is optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z³ groups;

R² is a 6-membered aryl, 5-membered heteroaryl or 6-membered heteroaryl,wherein any 6-membered aryl, 5-membered heteroaryl or 6-memberedheteroaryl of R² is optionally substituted with one or more (e.g. 1, 2or 3) Z⁴ groups;

each R^(3a) and R^(3b) is independently selected from H, halogen,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₆)heteroalkyl,heteroaryl(C₁-C₆)alkyl-, heterocyclyl(C₁-C₆)alkyl-, —NR_(a)R_(b), and—NR_(c)OR_(d); or R^(3a) and R^(3b) together with the carbon to whichthey are attached form a (C₃-C₆)carbocycle;

R⁴ is selected from H, (C₁-C₆)alkyl, (C₃-C₆)carbocycle,aryl(C₁-C₆)alkyl- and heteroaryl(C₁-C₆)alkyl-;

R_(a) and R_(b) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R_(a) and R_(b) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

each R_(c) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R_(d) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl, aryl,haloaryl, haloheteroaryl, haloheterocycle, (C₁-C₈)haloalkyl and(C₁-C₈)heteroalkyl;

each Z¹ is independently selected from (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₇)carbocycle, aryl, heteroaryl, heterocycle and —OR_(n1), whereinany (C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle of Z¹ isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(1a) orZ^(1b) groups and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z is optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z^(1a) groups;

each Z^(1a) is independently selected from (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n2), —OC(O)R_(p2),—OC(O)NR_(q2)R_(r2), —SR_(n2), —S(O)R_(p2), —S(O)₂OH, —S(O)₂R_(p2),—S(O)₂NR_(q2)R_(r2), —NR_(q2)R_(r2), —NR_(n2)COR_(p2),—NR_(n2)CO₂R_(p2), —NR_(n2)CONR_(q2)R_(r2), —NR_(n2)S(O)₂R_(p2),—NR_(n2)S(O)₂OR_(p2), —NR_(n2)S(O)₂NR_(q2)R_(r2), NO₂, —C(O)R_(r2),—C(O)OR_(n2), and, —C(O)NR_(q2)R_(r2), wherein any (C₃-C₇)carbocycle,aryl, heteroaryl and heterocycle of Z^(1a) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups;

each Z^(1b) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl, wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z^(1b) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(1c) groups;

each Z^(c) is independently selected from (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n3), —OC(O)R_(p3),—OC(O)NR_(q3)R_(r3), —SR_(n3), —S(O)R_(p3), —S(O)₂OH, —S(O)₂R_(p3),—S(O)₂NR_(q3)R_(r3), —NR_(q3)R_(r3), —NR_(n3)COR_(p3),—NR_(n3)CO₂R_(r3), —NR_(n3)CONR_(q3)R_(r3), —NR_(n3)S(O)₂R_(p3),—NR_(n3)S(O)₂OR_(p3), —NR_(n3)S(O)₂NR_(q3)R_(r3), NO₂, —C(O)R_(n3),—C(O)OR_(n3), —C(O)NR_(q3)R_(r3), haloaryl, haloheteroaryl,haloheterocycle and (C₁-C₈)heteroalkyl;

each Z^(1d) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl and (C₁-C₈)haloalkyl;

each R_(n1) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and aryl,wherein any (C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle ofR_(n1) is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(1a) or Z^(1b) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of R_(r1) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(1a) groups;

each R_(n2) is independently selected from H, (C₁-C₈)alkyl,(C₂—C)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(n2) is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(n2) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(1c) groups;

each R_(p2) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and aryl,wherein any (C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle ofR_(p2) is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(1c) or Z^(1d) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of R_(p2) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(1c) groups;

R_(q2) and R_(r2) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(q2) or R_(r2) is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(q2) or R_(r2) isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(1c)groups, or R_(q2) and R_(r2) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups;

each R_(n3) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R_(p3) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl, aryl,haloaryl, haloheteroaryl, haloheterocycle, (C₁-C₈)haloalkyl and(C₁-C₈)heteroalkyl;

R_(q3) and R_(r3) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R_(q3) and R_(r3) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

each Z² is independently selected from (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,(C₃-C₇)carbocycle, halogen, CN, OH and —O(C₁-C₆)alkyl;

each Z³ is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, aryl, heteroaryl, heterocycle,halogen, —CN, —OR_(n4), —OC(O)R_(p4), —OC(O)NR_(q4)R_(r4), —SR_(n4),—S(O)R_(p4), —S(O)₂OH, —S(O)₂R_(p4), —S(O)₂NR_(q4)R_(r4),—NR_(q4)R_(r4), —NR₄COR_(p4), —NR_(n4)CO₂R_(p4),—NR_(n4)CONR_(q4)R_(r4), —NR_(n4)S(O)₂R_(p4), —NR_(n4)S(O)₂OR_(p4),—NR_(n4)S(O)₂NR_(q4)R_(r4), NO₂, —C(O)R_(n4), —C(O)OR_(n4), and—C(O)NR_(q4)R_(r4), wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of Z³ is optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z^(3a) or Z^(3b) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of Z³ is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z^(3a) groups;

each Z^(3a) is independently selected from (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n5), —OC(O)R_(p5),—OC(O)NR_(q5)R_(r5), —SR₅, —S(O)R_(p5), —S(O)₂OH, —S(O)₂R_(p5),—S(O)₂NR_(q5)R_(r5), —NR_(q5)R_(r5), —NR_(n5)COR_(p5),—NR_(n5)CO₂R_(p5), —NR_(n5)CONR_(q5)R_(r5), —NR_(n5)S(O)₂R_(p5),—NR_(n5)S(O)₂OR_(p5), —NR_(n5)S(O)₂NR_(q5)R_(r5), NO₂, —C(O)R_(n5),—C(O)OR_(n5), and —C(O)NR_(q5)R_(r5), wherein any (C₃-C₇)carbocycle,aryl, heteroaryl and heterocycle of Z^(3a) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(3c) or Z^(3d) groups;

each Z^(3b) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl, wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z^(3b) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(3c) groups;

each Z^(3c) is independently selected from (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n6), —OC(O)R_(p6),—OC(O)NR_(q6)R_(r6), —SR_(n6), —S(O)R_(p6), —S(O)₂OH, —S(O)₂R_(p6),—S(O)₂NR_(q6)R_(r6), —NR_(q6)R_(r6), —NR_(n6)COR_(p6),—NR_(n6)CO₂R_(p6), —NR_(n6)CONR_(q6)R_(r6), —NR_(n6)S(O)₂R_(p6),—NR_(n6)S(O)₂OR_(p6), —NR_(n6)S(O)₂ NR_(q6)R_(r6), NO₂, —C(O)R_(n6),—C(O)OR_(n6), —C(O)NR_(q6)R_(r6), haloaryl, haloheteroaryl,haloheterocycle and (C₁-C₈)heteroalkyl;

each Z^(3d) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, and (C₁-C₈)haloalkyl;

each R_(n4) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(n4) is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(3a) or Z^(3b) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(n4) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(3a) groups;

each R_(p4) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and aryl,wherein any (C₃-C₇)carbocycle, aryl, heteroaryl, or heterocycle ofR_(p4) is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(3a) or Z^(3b) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl or(C₂-C₈)alkynyl of R_(p4) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(3a) groups;

R_(q4) and R_(r4) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(q4) or R_(r4) is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(3a) or Z^(3b) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(q4) or R_(r4) isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(3a)groups, or R_(q4) and R_(r4) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(3a) or Z^(3b) groups;

each R_(n5) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(n5) is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(3c) or Z^(3d) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(n5) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(3c) groups;

each R_(p5) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and aryl,wherein any (C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle ofR_(p5) is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(3c) or Z^(3d) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of R_(p5) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(3c) groups;

R_(q5) and R_(r5) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(q5) or R_(r5) is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(3c) or Z^(3d) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(q5) or R_(r5) isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(3c)groups, or R_(q5) and R_(r5) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(3c) or Z^(3d) groups;

each R_(n6) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R_(p6) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl, aryl,haloaryl, haloheteroaryl, haloheterocycle, (C₁₋C₈)haloalkyl and(C₁-C₈)heteroalkyl;

R_(q6) and R_(r6) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R_(q6) and R_(r6) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

each Z⁴ is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, aryl, heteroaryl, heterocycle,halogen, —CN, —OR_(n8), —OC(O)R_(p8), —OC(O)NR_(q8)R_(r8), —SR_(n8),—S(O)R_(p8), —S(O)₂OH, —S(O)₂R_(p8), —S(O)₂NR_(q8)R_(r8),—NR_(q8)R_(r8), —NR_(n8)COR_(p8), —NR_(n8)CO₂R_(p8),—NR₈CONR_(q8)R_(r8), —NR_(n8)S(O)₂R_(p8), —NR_(n8)S(O)₂OR_(p8),—NR_(n8)S(O)₂ NR_(q8)R_(r8), NO₂, —C(O)R_(n8), —C(O)OR_(n8), and—C(O)NR_(q8)R_(r8), wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of Z⁴ is optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z^(4c) or Z^(4d) groups and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of Z⁴ is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z^(4c) groups;

each Z^(4c) is independently selected from of (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n9), —OC(O)R_(p9),—OC(O)NR_(q9)R_(r9), —SR_(n9), —S(O)R_(p9), —S(O)₂OH, —S(O)₂R_(p9),—S(O)₂NR_(q9)R^(r9), —NR_(q9)R_(r9), —NR_(n9)COR_(p9),—NR_(n9)CO₂R_(p9), —NR_(n9)CONR_(q9)R_(r9), —NR_(n9)S(O)₂R_(p9),—NR_(n9)S(O)₂OR_(p9), —NR_(n9)S(O)₂ NR_(q9)R_(r9), NO₂, —C(O)R_(n9),—C(O)OR_(n9), —C(O)NR_(q9)R_(r9), haloaryl, haloheteroaryl,haloheterocycle and (C₁-C₈)heteroalkyl;

each Z^(4d) is independently selected from of (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl and (C₁-C₈)haloalkyl;

each R_(n8) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(n8) is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(4c) or Z^(4d) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl or (C₂-C₈)alkynyl of R_(n8) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(4c) groups;

each R_(p8) is independently selected from (C₁-C₈)alkyl,(C₁-C₆)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle,heterocycle, heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl,heteroaryl and heterocycle of R_(p8) is optionally substituted with oneor more (e.g. 1, 2, 3, 4 or 5) Z^(4c) or Z^(4d) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(p8) is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(4c) groups;

R_(q8) and R_(r8) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(q8) or R_(r8) is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(4c) or Z^(4d) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(q8) or R_(r8) isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(4c)groups, or R_(q8) and R_(r8) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(4c) or Z^(4d) groups;

each R_(n9) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R_(p9) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl, aryl,haloaryl, haloheteroaryl, haloheterocycle, (C₁-C₈)haloalkyl and(C₁-C₈)heteroalkyl; and

R_(q9) and R_(r9) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl; or R_(q9) and R_(r9) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

or a salt thereof.

In one embodiment, the invention provides a compound of the inventionwhich is a compound of formula I′:

wherein:

A is a 6-membered heteroaryl comprising one or two nitrogens, whereinthe 6-membered heteroaryl is substituted with one Z¹ group andoptionally substituted with one or more (e.g. 1, 2, or 3) Z² groups;

W is CR^(3a)R^(3b), O or NR⁴;

R¹ is aryl, heteroaryl or heterocycle, wherein any aryl, heteroaryl orheterocycle of R¹ is optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z³ groups;

R² is a 6-membered aryl, 5-membered heteroaryl or 6-membered heteroaryl,wherein any 6-membered aryl, 5-membered heteroaryl or 6-memberedheteroaryl of R² is optionally substituted with one or more (e.g. 1, 2or 3) Z⁴ groups;

each R^(3a) and R^(3b) is independently selected from H, halogen,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₁-C₆)heteroalkyl,—(C₁-C₆)alkylheteroaryl, —(C₁-C₆)alkylheterocyclyl, —NR_(a)R_(b), and—NR_(c)COR_(d); or R^(3a) and R^(3b) together with the carbon to whichthey are attached form a (C₃-C₆)carbocycle;

R⁴ is selected from H, (C₁-C₆)alkyl, (C₃-C₆)carbocycle,—(C₁-C₆)alkylaryl and —(C₁-C₆)alkylheteroaryl;

R_(a) and R_(b) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R_(a) and R_(b) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

each R_(c) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R_(d) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl, aryl,haloaryl, haloheteroaryl, haloheterocycle, (C₁-C₈)haloalkyl and(C₁-C₈)heteroalkyl;

each Z¹ is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, aryl, heteroaryl, heterocycle and—OR_(n1), wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of Z¹ is optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z^(1a) or Z^(1b) groups and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of Z¹ is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z^(1a) groups;

each Z^(1a) is independently selected from (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n2), —OC(O)R_(p2),—OC(O)NR_(q2)R_(r2), —SR_(n2), —S(O)R_(p2), —S(O)₂OH, —S(O)₂R_(p2),—S(O)₂NR_(q2)R_(r2), —NR_(q2)R_(r2), —NR_(n2)COR_(p2),—NR_(n2)CO₂R_(p2), —NR_(n2)CONR_(q2)R_(r2), —NR_(n2)S(O)₂R_(p2),—NR_(n2)S(O)₂OR_(p2), —NR_(n2)S(O)₂NR_(q2)R_(r2), NO₂, —C(O)R_(n2),—C(O)OR_(n2), and, —C(O)NR_(p2)R_(q2), wherein any (C₃-C₇)carbocycle,aryl, heteroaryl and heterocycle of Z^(1a) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups;

each Z^(1b) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl, wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z^(1b) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(1c) groups;

each Z^(1c) is independently selected from (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n3), —OC(O)R_(p3),—OC(O)NR_(q3)R_(r3), —SR_(n3), —S(O)R_(p3), —S(O)₂OH, —S(O)₂R_(p3),—S(O)₂NR_(q3)R_(r3), —NR_(q3)R_(r3), —NR_(n3)COR_(p3),—NR_(n3)CO₂R_(p3), —NR_(n3)CONR_(q3)R_(r3), —NR_(n3)S(O)₂R_(p3),—NR_(n3)S(O)₂OR_(p3), —NR_(n3)S(O)₂NR_(q3)R_(r3), NO₂, —C(O)R_(n3),—C(O)OR_(n3), —C(O)NR_(q3)R_(r3), haloaryl, haloheteroaryl,haloheterocycle and (C₁-C₈)heteroalkyl;

each Z^(1d) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl and (C₁-C₈)haloalkyl;

each R_(n1) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and aryl,wherein any (C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle ofR_(n1) is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(1a) or Z^(1b) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of R_(n1) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(1a) groups;

each R_(n2) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(n2) is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(n2) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(1c) groups;

each R_(p2) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and aryl,wherein any (C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle ofR_(p2) is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(1c) or Z^(1d) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of R_(p2) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(1c) groups;

R_(q2) and R_(r2) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(q2) or R_(r2) is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(q2) or R_(r2) isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(1c)groups, or R_(q2) and R_(r2) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(1c) or Z^(1d) groups;

each R_(n3) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R_(p3) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl, aryl,haloaryl, haloheteroaryl, haloheterocycle, (C₁₋C₈)haloalkyl and(C₁-C₈)heteroalkyl;

R_(q3) and R_(r3) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R_(q3) and R_(r3) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

each Z² is independently selected from (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,(C₃-C₇)carbocycle, halogen, CN, OH and —O(C₁-C₆)alkyl;

each Z³ is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, aryl, heteroaryl, heterocycle,halogen, —CN, —OR_(n4), —OC(O)R_(p4), —OC(O)NR_(q4)R_(r4), —SR_(n4),—S(O)R_(p4), —S(O)₂OH, —S(O)₂R_(p4), —S(O)₂NR_(q4)R_(r4),—NR_(q4)R_(r4), —NR_(n4)COR_(p4), —NR_(n4)CO₂R_(p4),—NR_(n4)CONR_(q4)R_(r4), —NR_(n4)S(O)₂R_(p4), —NR_(n4)S(O)₂OR_(p4),—NR_(n4)S(O)₂NR_(q4)R_(r4), NO₂, —C(O)R_(n4), —C(O)OR_(n4), and—C(O)NR_(q4)R_(r4), wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of Z³ is optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z^(3a) or Z^(3b) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of Z³ is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z^(3a) groups;

each Z^(3a) is independently selected from (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n5), —OC(O)R_(p5),—OC(O)NR_(q5)R_(r5), —SR_(n5), —S(O)R_(p5), —S(O)₂OH, —S(O)₂R_(p5),—S(O)₂NR_(q5)R_(r5), —NR_(q5)R_(r5), —NR_(n5)COR_(p5),—NR_(n5)CO₂R_(p5), —NR_(n5)CONR_(q5)R_(r5), —NR_(n5)S(O)₂R_(p5),—NR_(n5)S(O)₂OR_(p5), —NR_(n5)S(O)₂NR_(q5)R_(r5), NO₂, —C(O)R_(n5),—C(O)OR_(n5), and —C(O)NR_(q5)R_(r5), wherein any (C₃-C₇)carbocycle,aryl, heteroaryl and heterocycle of Z^(3a) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(3c) or Z^(3d) groups;

each Z^(3b) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl, wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z^(3b) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(3c) groups;

each Z^(3c) is independently selected from (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n6), —OC(O)R_(p6),—OC(O)NR_(q6)R_(r6), —SR_(n6), —S(O)R_(p6), —S(O)₂OH, —S(O)₂R_(p6),—S(O)₂NR_(q6)R_(r6), —NR_(g6)R_(r6), —NR_(n6)COR_(p6),—NR_(n6)CO₂R_(p6), —NR_(n6)CONR_(q6)R_(r6), —NR_(n6)S(O)₂R_(p6),—NR_(n6)S(O)₂OR_(p6), —NR_(n6)S(O)₂ NR_(q6)R_(r6), NO₂, —C(O)R_(n6),—C(O)OR_(n6), —C(O)NR_(q6)R_(r6), haloaryl, haloheteroaryl,haloheterocycle and (C₁-C₈)heteroalkyl;

each Z^(3d) is independently selected from of (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, and (C₁-C₈)haloalkyl;

each R_(n4) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(n4) is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(3a) or Z^(3b) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(n4) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(3a) groups;

each R_(p4) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and aryl,wherein any (C₃-C₇)carbocycle, aryl, heteroaryl, or heterocycle ofR_(p4) is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(3a) or Z^(3b) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl or(C₂-C₈)alkynyl of R_(p4) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(3a) groups;

R_(q4) and R_(r4) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(q4) or R_(r4) is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(3a) or Z^(3b) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(q4) or R_(r4) isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(3a)groups, or R_(q4) and R_(r4) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(3a) or Z^(3b) groups;

each R_(n5) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(n5) is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(3c) or Z^(3d) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(n5) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(3c) groups;

each R_(p5) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and aryl,wherein any (C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle ofR_(p5) is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z^(3c) or Z^(3d) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of R_(p5) is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z^(3c) groups;

R_(q5) and R_(r5) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(q5) or R_(r5) is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(3c) or Z^(3d) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(q5) or R_(r5) isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z³Cgroups, or R_(q5) and R_(r5) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(3c) or Z^(3d) groups;

each R_(n6) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R_(p6) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl, aryl,haloaryl, haloheteroaryl, haloheterocycle, (C₁-C₈)haloalkyl and(C₁-C₈)heteroalkyl;

R_(q6) and R_(r6) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R_(q6) and R_(r6) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

each Z⁴ is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, aryl, heteroaryl, heterocycle,halogen, —CN, —OR_(n8), —OC(O)R_(p8), —OC(O)NR_(q8)R_(r8), —SR_(n8),—S(O)R_(p8), —S(O)₂OH, —S(O)₂R_(p8), —S(O)₂NR_(q8)R_(r8),—NR_(q8)R_(r8), —NR_(n8)COR_(p8), —NR_(n8)CO₂R_(p8),—NR_(n8)CONR_(q8)R_(r8), —NR_(n8)S(O)₂R_(p8), —NR_(n8)S(O)₂OR_(p8),—NR_(n8)S(O)₂ NR_(q8)R_(r8), NO₂, —C(O)R_(n8), —C(O)OR_(n5), and—C(O)NR_(q8)R_(r8), wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of Z⁴ is optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z^(4c) or Z^(4d) groups and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of Z⁴ is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z^(4c) groups;

each Z^(4c) is independently selected from of (C₃-C₇)carbocycle, aryl,heteroaryl, heterocycle, halogen, —CN, —OR_(n9), —OC(O)R_(p9),—OC(O)NR_(q9)R_(r9), —SR_(n9), —S(O)R_(p9), —S(O)₂OH, —S(O)₂R_(p9),—S(O)₂NR_(q9)R_(r9), —NR_(q9)R_(r9), —NR_(n9)COR_(p9),—NR_(n9)CO₂R_(p9), —NR_(n9)CONR_(q9)R_(r9), —NR_(n9)S(O)₂R_(p9),—NR_(n9)S(O)₂OR_(p9), —NR_(n9)S(O)₂ NR_(q9)R_(r9), NO₂, —C(O)R_(n9),—C(O)OR_(n9), —C(O)NR_(q9)R_(r9), haloaryl, haloheteroaryl,haloheterocycle and (C₁-C₈)heteroalkyl;

each Z^(4d) is independently selected from of (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl and (C₁-C₈)haloalkyl;

each R_(n8) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(n8) is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(4c) or Z^(4d) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl or (C₂-C₈)alkynyl of R_(n8) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z^(4c) groups;

each R_(p8) is independently selected from (C₁-C₈)alkyl,(C₁-C₆)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle,heterocycle, heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl,heteroaryl and heterocycle of R_(p8) is optionally substituted with oneor more (e.g. 1, 2, 3, 4 or 5) Z^(4c) or Z^(4d) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(p8) is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(4c) groups;

R_(q8) and R_(r8) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and aryl, wherein any (C₃-C₇)carbocycle, aryl, heteroaryl andheterocycle of R_(q8) or R_(r8) is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z^(4c) or Z^(4d) groups, and wherein any(C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(q8) or R_(r8) isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z^(4c)groups, or R_(q8) and R_(r8) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z^(4c) or Z^(4d) groups;

each R_(n9) is independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl;

each R_(p9) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl, aryl,haloaryl, haloheteroaryl, haloheterocycle, (C₁-C₈)haloalkyl and(C₁-C₈)heteroalkyl; and

R_(q9) and R_(r9) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl; or R_(q9) and R_(r9) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle;

or a salt thereof.

General Synthetic Procedures

Schemes 1, 2 and 3 describe methods that can be used to preparecompounds of formula I.

Scheme 1 describes a general synthetic route which can be used toprepare compounds of formula I. An appropriately substituted heteroarylnitrile may be reacted with a Grignard reagent followed by reduction toprovide compounds of formula A2. The amine can be coupled to a varietyof carboxcyclic acid derivatives to provide compounds of formula A3.

Scheme 2 describes a general stereoselective route which can be used toprepare compounds of formula I. Heteroaryl aldehydes of formula B1 canbe condensed with a chiral auxiliary to provide a stereoselectiveaddition of a nucleophilic reagent. Depicted in Scheme 2 is thecondensation of an appropriately substituted heterocyclic aldehyde B1with tert-butane sulfonamide and the addition of a Grignard reagent toprovide a mixture of B3 and B4 enriched in B3. This mixture may beseparated by column chromatography on silica gel to provide purediastereomers. Removal of the auxiliary provides amines B5 and B6 whichcan be coupled to a variety of carboxylic acids to provide compounds offormula B7 and B8.

Scheme 3 describes a general stereoselective route which can be used toprepare compounds of formula I. Heteroaryl aldehydes of formula B1 canbe condensed with a chiral auxiliary to provide a stereoselectiveaddition of a nucleophilic reagent. Depicted in Scheme 3 is thecondensation of an bromo-substituted heterocyclic aldehyde C1 with (S)tert-butane sulfonamide and the addition of a Grignard reagent toprovide a mixture of C3 and C4 enriched in C3. This mixture may beseparated by column chromatography on silica gel to provide purediastereomers. Removal of the auxiliary provides amines C5 and C6 whichcan be coupled to a variety of carboxylic acids to provide heteroarylcompounds of formula C7 and C8. Diversification of C7 and C8 may beaccomplished by a variety of methods including metal catalyzed crosscoupling reactions such as Suzuki couplings and Sonogashira couplings.

Prodrugs

In one embodiment, the invention provides for a prodrug of a compound ofthe invention. The term “prodrug” as used herein refers to any compoundthat when administered to a biological system generates a compound ofthe invention that inhibits the replication of HIV (“the activeinhibitory compound”). The compound may be formed from the prodrug as aresult of: (i) spontaneous chemical reaction(s), (ii) enzyme catalyzedchemical reaction(s), (iii) photolysis, and/or (iv) metabolic chemicalreaction(s).

“Prodrug moiety” refers to a labile functional group which separatesfrom the active inhibitory compound during metabolism, systemically,inside a cell, by hydrolysis, enzymatic cleavage, or by some otherprocess (Bundgaard, Hans, “Design and Application of Prodrugs” in ATextbook of Drug Design and Development (1991), P. Krogsgaard-Larsen andH. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymeswhich are capable of an enzymatic activation mechanism with the prodrugcompounds of the invention include, but are not limited to, amidases,esterases, microbial enzymes, phospholipases, cholinesterases, andphosphases. Prodrug moieties can serve to enhance solubility, absorptionand lipophilicity to optimize drug delivery, bioavailability andefficacy. A prodrug moiety may include an active metabolite or drugitself.

Exemplary prodrug moieties include the hydrolytically sensitive orlabile acyloxymethyl esters —CH₂OC(═O)R⁹⁹ and acyloxymethyl carbonates—CH₂OC(═O)OR⁹⁹ where R⁹⁹ is C₁-C₆ alkyl, C₁-C₆ substituted alkyl, C₆-C₂₀aryl or C₆-C₂₀ substituted aryl. The acyloxyalkyl ester was first usedas a prodrug strategy for carboxylic acids and then applied tophosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72:324; also U.S. Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756.Subsequently, the acyloxyalkyl ester was used to deliver phosphonicacids across cell membranes and to enhance oral bioavailability. A closevariant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester(carbonate), may also enhance oral bioavailability as a prodrug moietyin the compounds of the combinations of the invention. An exemplaryacyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH₂OC(═O)C(CH₃)₃. Anexemplary acyloxymethyl carbonate prodrug moiety ispivaloyloxymethylcarbonate (POC) —CH₂OC(═O)OC(CH₃)₃.

Aryl esters of phosphorus groups, especially phenyl esters, are reportedto enhance oral bioavailability (De Lombaert et al. (1994) J. Med Chem.37: 498). Phenyl esters containing a carboxylic ester ortho to aphosphate have also been described (Khamnei and Torrence, (1996) J. MedChem. 39:4109-4115). Benzyl esters are reported to generate parentphosphonic acids. In some cases, substituents at the ortho- orpara-position may accelerate the hydrolysis. Benzyl analogs with anacylated phenol or an alkylated phenol may generate the phenoliccompound through the action of enzymes, e.g., esterases, oxidases, etc.,which in turn undergoes cleavage at the benzylic C—O bond to generatephosphoric acid and a quinone methide intermediate. Examples of thisclass of prodrugs are described by Mitchell et al. (1992) J. Chem. Soc.Perkin Trans. II 2345; Glazier WO 91/19721. Still other benzylicprodrugs have been described containing a carboxylic ester-containinggroup attached to the benzylic methylene (Glazier WO 91/19721).Thio-containing prodrugs are reported to be useful for the intracellulardelivery of phosphonate drugs. These proesters contain an ethylthiogroup in which the thiol group is either esterified with an acyl groupor combined with another thiol group to form a disulfide.Deesterification or reduction of the disulfide generates the free thiointermediate which subsequently breaks down to the phosphoric acid andepisulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria etal. (1996) J. Med Chem. 39: 4958).

Combination Therapy

In one embodiment, the invention provides for a method for treating anHIV infection, comprising administering to a patient in need thereof atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt, thereof, in combination with atherapeutically effective amount of one or more additional therapeuticagents which are suitable for treating an HIV infection.

In one embodiment, the invention provides pharmaceutical compositionscomprising a compound of the present invention, or a pharmaceuticallyacceptable salt thereof, in combination with at least one additionaltherapeutic agent, and a pharmaceutically acceptable carrier. Forexample, the therapeutic agent used in combination with the compound ofthe present invention can be any anti-HIV agent.

In one embodiment, the invention provides pharmaceutical compositionscomprising a compound of the present invention, or a pharmaceuticallyacceptable salt thereof, in combination with at least one additionaltherapeutic agent selected from the group consisting of HIV proteaseinhibiting compounds, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside inhibitors of reverse transcriptase, HIVnucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5inhibitors, capsid polymerization inhibitors, and other drug fortreating HIV, and combinations thereof, and a pharmaceuticallyacceptable carrier.

In another embodiment, the invention provides pharmaceuticalcompositions comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, in combination with at leastone additional therapeutic agent selected from the group consisting of:

(1) HIV protease inhibiting compounds selected from the group consistingof amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir,ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir,TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423,RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35,and AG 1859;

(2) HIV non-nucleoside inhibitors of reverse transcriptase selected fromthe group consisting of capravirine, emivirine, delaviridine, efavirenz,nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961,DPC-963, MIV-150, and TMC-120, rilpivirene, BILR 355 BS, VRX 840773,UK-453061, and RDEA806;

(3) HIV nucleoside inhibitors of reverse transcriptase selected from thegroup consisting of zidovudine, emtricitabine, didanosine, stavudine,zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine,MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil,apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine tidoxil(formerly HDP 99.0003);

(4) HIV nucleotide inhibitors of reverse transcriptase selected from thegroup consisting of tenofovir, tenofovir disoproxil fumarate, GS-7340(Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) orCMX-157 (Chimerix)

(5) HIV integrase inhibitors selected from the group consisting ofcurcumin, derivatives of curcumin, chicoric acid, derivatives ofchicoric acid, 3,5-dicaffeoylquinic acid, derivatives of3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives ofaurintricarboxylic acid, caffeic acid phenethyl ester, derivatives ofcaffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin,quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, andL-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA011 and dolutegravir;

(6) gp41 inhibitors selected from the group consisting of enfuvirtide,sifuvirtide, FB006M, and TRI-1144;

(7) the CXCR4 inhibitor AMD-070;

(8) the entry inhibitor SP01A;

(9) the gp120 inhibitor BMS-488043;

(10) the G6PD and NADH-oxidase inhibitor immunitin;

(11) CCR5 inhibitors selected from the group consisting of aplaviroc,vicriviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), andCCR5mAb004;

(12) other drugs for treating HIV selected from the group consisting ofBAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1,PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221HIV, DEBIO-025, BAY 50-4798, MDXO10 (ipilimumab), PBS 119, ALG 889, andPA-1050040 (PA-040).

In another embodiment, the invention provides pharmaceuticalcompositions comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, in combination with two,three, four or more additional therapeutic agents. For example, acompound of the present invention, or a pharmaceutically acceptablesalt, thereof, is combined with two, three, four or more additionaltherapeutic agents selected from the classes of HIV protease inhibitingcompounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside inhibitors of reverse transcriptase, HIV nucleotideinhibitors of reverse transcriptase, HIV integrase inhibitors, gp41inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsidpolymerization inhibitors and other drug for treating HIV. The two,three four or more additional therapeutic agents can be differenttherapeutic agents selected from the same class of therapeutic agents,or they can be selected from different classes of therapeutic agents.

In one embodiment, the invention provides for a combinationpharmaceutical agent comprising:

a) a compound of the invention (e.g. a compound of Formula I), or apharmaceutically acceptable salt, thereof; and

b) at least one additional active agent which is suitable for treatingan HIV infection.

In another embodiment, the invention provides a combinationpharmaceutical agent comprising:

a) a compound of the invention (e.g. a compound of Formula I), or apharmaceutically acceptable salt thereof; and

b) at least one additional therapeutic agent selected from the groupconsisting of HIV protease inhibiting compounds, HIV non-nucleosideinhibitors of reverse transcriptase, HIV nucleoside inhibitors ofreverse transcriptase, HIV nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors and other drug for treating HIV.

It is also possible to combine any compound of the invention with one ormore other active therapeutic agents in a unitary dosage form forsimultaneous or sequential administration to a patient. The combinationtherapy may be administered as a simultaneous or sequential regimen.When administered sequentially, the combination may be administered intwo or more administrations.

It is also possible to co-administer a compound of the invention withone or more other active therapeutic agents. Co-administration of acompound of the invention with one or more other active therapeuticagents generally refers to simultaneous or sequential administration ofa compound of the invention and one or more other active therapeuticagents, such that therapeutically effective amounts of the compound ofthe invention and one or more other active therapeutic agents are bothpresent in the body of the patient.

Co-administration includes administration of unit dosages of thecompounds of the invention before or after administration of unitdosages of one or more other active therapeutic agents, for example,administration of the compounds of the invention within seconds,minutes, or hours of the administration of one or more other activetherapeutic agents. For example, a unit dose of a compound of theinvention can be administered first, followed within seconds or minutesby administration of a unit dose of one or more other active therapeuticagents. Alternatively, a unit dose of one or more other therapeuticagents can be administered first, followed by administration of a unitdose of a compound of the invention within seconds or minutes. In somecases, it may be desirable to administer a unit dose of a compound ofthe invention first, followed, after a period of hours (e.g., 1-12hours), by administration of a unit dose of one or more other activetherapeutic agents. In other cases, it may be desirable to administer aunit dose of one or more other active therapeutic agents first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound of the invention.

The combination therapy may provide “synergy” and “synergistic effect”,i.e. the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by some other regimen.When delivered in alternation therapy, a synergistic effect may beattained when the compounds are administered or delivered sequentially,e.g., in separate tablets, pills or capsules, or by different injectionsin separate syringes. In general, during alternation therapy, aneffective dosage of each active ingredient is administered sequentially,i.e. serially, whereas in combination therapy, effective dosages of twoor more active ingredients are administered together.

In yet another embodiment, the present application provides a method fortreating an HIV infection comprising administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention, or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents selected from the group consisting of HIV proteaseinhibiting compounds, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside inhibitors of reverse transcriptase, HIVnucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5inhibitors, capsid polymerization inhibitors, and other drug fortreating HIV.

In yet another embodiment, the present application provides a method fortreating an HIV infection comprising administering to a patient in needthereof a therapeutically effective amount of a compound of the presentinvention, or a pharmaceutically acceptable salt, thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents selected from the group consisting of:

(1) HIV protease inhibiting compounds selected from the group consistingof amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir,ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir,TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423,RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35,and AG 1859;

(2) HIV non-nucleoside inhibitors of reverse transcriptase selected fromthe group consisting of capravirine, emivirine, delaviridine, efavirenz,nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961,DPC-963, MIV-150, and TMC-120, rilpivirene, BILR 355 BS, VRX 840773,UK-453061, and RDEA806;

(3) HIV nucleoside inhibitors of reverse transcriptase selected from thegroup consisting of zidovudine, emtricitabine, didanosine, stavudine,zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine,MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil,apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine tidoxil(formerly HDP 99.0003);

(4) HIV nucleotide inhibitors of reverse transcriptase selected from thegroup consisting of tenofovir, tenofovir disoproxil fumarate, GS-7340(Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) orCMX-157 (Chimerix)

(5) HIV integrase inhibitors selected from the group consisting ofcurcumin, derivatives of curcumin, chicoric acid, derivatives ofchicoric acid, 3,5-dicaffeoylquinic acid, derivatives of3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives ofaurintricarboxylic acid, caffeic acid phenethyl ester, derivatives ofcaffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin,quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, andL-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA011 and dolutegravir;

(6) gp41 inhibitors selected from the group consisting of enfuvirtide,sifuvirtide, FB006M, and TRI-1144;

(7) the CXCR4 inhibitor AMD-070;

(8) the entry inhibitor SP01A;

(9) the gp120 inhibitor BMS-488043;

(10) the G6PD and NADH-oxidase inhibitor immunitin;

(11) CCR5 inhibitors selected from the group consisting of aplaviroc,vicriviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), andCCR5mAb004;

(12) other drugs for treating HIV selected from the group consisting ofBAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1,PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, andPA-1050040 (PA-040).

Pharmaceutical Formulations

The compounds of this invention are formulated with conventionalcarriers and excipients, which will be selected in accord with ordinarypractice. Tablets will contain excipients, glidants, fillers, bindersand the like. Aqueous formulations are prepared in sterile form, andwhen intended for delivery by other than oral administration generallywill be isotonic. All formulations will optionally contain excipientssuch as those set forth in the Handbook of Pharmaceutical Excipients(1986). Excipients include ascorbic acid and other antioxidants,chelating agents such as EDTA, carbohydrates such as dextrin,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. The pH of the formulations ranges from about 3 to about 11, but isordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the inventioncomprise at least one active ingredient, as above defined, together withone or more acceptable carriers and optionally other therapeuticingredients. The carrier(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation andphysiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

For administration to the eye or other external tissues e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w (including active ingredient(s) in a range between 0.1%and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention compriseone or more compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyl oxidewith a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye dropswherein the active ingredient is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active ingredient. Theactive ingredient is preferably present in such formulations in aconcentration of 0.5 to 20%, advantageously 0.5 to 10% particularlyabout 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention can also be formulated to provide controlledrelease of the active ingredient to allow less frequent dosing or toimprove the pharmacokinetic or toxicity profile of the activeingredient. Accordingly, the invention also provides compositionscomprising one or more compounds of the invention formulated forsustained or controlled release.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses), the method of delivery, and thepharmaceutical formulation, and will be determined by the clinicianusing conventional dose escalation studies.

Routes of Administration

One or more compounds of the invention (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds of this invention is that they are orally bioavailableand can be dosed orally.

The antiviral properties of a compound of the invention may bedetermined using Test A described below.

Test A: Antiviral Assay in MT4 Cells

For the antiviral assay, 40 μL of 1× test concentration of 3-foldserially diluted compound in culture medium with 10% FBS was added toeach well of a 384-well plate (10 concentrations) in quadruplicate. MT-4cells were next mixed with HIV-IIIb at an m.o.i of 0.003 for 1 hour,after which time 35 μL of virus/cell mixture (2000 cells) wasimmediately added to each well containing 40 μL of diluted compound. Theplates were then incubated at 37° C. for 5 days. After 5 days ofincubation, 25 μl of 2× concentrated CellTiter-Glo™ Reagent (catalog #G7571, Promega Biosciences, Inc., Madison, Wis.) was added to each wellcontaining MT-4 cells. Cell lysis was carried out by incubating at roomtemperature for 10 min and then chemiluminescence was read. EC50 valueswere defined as the compound concentration that caused a 50% decrease inluminescence signal, a measure of HIV-1 replication. Percent inhibitionof virus-induced cell killing calculated from the dose response curve at2 uM drug concentration is shown in the table below.

Test B: Cytotoxicity Assay

Compound cytotoxicity and the corresponding CC50 values was determinedusing the same protocol as described in the antiviral assay (Test A)except that uninfected cells were used.

Compounds of the present invention demonstrate antiviral activity asdepicted in the table below. Accordingly, the compounds of the inventionmay be useful for treating an HIV virus infection, treating AIDS or fordelaying the onset of AIDS or ARC symptoms. Shown below are thecorresponding values for CC50 and percent inhibition of virus-inducedcell killing in the presence of 2 uM drug concentration.

% inhibition CC50 Compound at 2 μM (nM)  1D 17 30766  2 29 14001  3 4021900  4 69 10299  5 76 32736  6 45 11424  7 18 17620  8 20 15707  9E 035914  10 0 12973  11 0 35671  12 0 8978  13G 97 25557  14 76 25450  150 28235  16 0 14004  17 70 13779  18 0 14595  19 25 14241  20 84 48268 21 28 15531  22 0 45696  23 0 13820  24 39 24822  25 71 11920  26 7024504  27 72 11952  28 93 25972  29 36 13232  30 76 11932  31 34 8633 32 94 19310  33 75 9750  34E 0 27812  35G 49 22398  36F 15 7201  36G 06931  37 84 34204  38D 3 42570  38E 86 28602  39 99 >47993  40 99 >48902 41 97 >53000  42 96 >53000  43 28 >53000  44 96 >52456  45 32 >53000 46 87 >53000  47 59 >53000  48 74 >53000  49 0 562  50D 106 16937  5152 >53000  52 92 13348  53 33 28268  54G 111 10343  55F 101 21646  56B 418889  57B 98 13318  58D 14 9996  59E 75 45084  60H 97 23982  61F 7417882  62 80 9984  63 22 14800  64 88 21071  65 33 11125  66 −2 16799 67 0 6458  68B 28 >53192  69 84 6687  70 56 51249  71 64 >53192  72 5616153  73 15 9794  74D 4 8470  75 17 10749  76 20 11515  77 65 12434  7811 7890  79F 19 >50627  80 0 >53192  81D 75 16742  82 114 19283  83 9225486  84 18 9046  85 9 43043  86 97 21450  87 101 21647  88E 44 >53192 89 73 10675  90F 13 34585  91B 17 22046  92 0 10286  93B 0 8141  94 342048  95C 14 14620  96 104 9625  97 27 33870  98 13 17954  99 0 >53192100 56 7828 101 29 12626 102D 50 21484 103 0 5170 104 32 15722 105 999084 107E 30 42789 108 13 >53000 109 50 9085 110 6 7611 111 41 9946 112B28 >53192 113 78 22275 114 32 >53192 116 72 >53192 117 89 8256 118 10835951 119 48 >53192 120 73 13828 121 68 9103 122G 101 19919 123E84 >53192 124C 77 20162 125 0 >53000 126 7 >53000 127C 97 31894 128 723549 129 0 10152 130D 39 15764 131C 47 10412 132 7 22253 133 1 >53000134 98 25170 135 53 21069 136D 88 27842 137 1 21734 138 30 24507 139 813954 140 0 >53000 141G 4 21761 142C 23 >53192 143 10 19885 14489 >53000 145 0 22394 146 66 20592 147 10 >53192 148 11 12278 1492 >53192 150 15 18420 151E 11 20301 152D 81 28392 153 10 17285 154 9036786 155 97 36975 156 30 39244 157 10 38312 158 0 8496 159 84 19108 16045 29334 161 0 9307 162E 37 >53192 163C 105 27367 164 2 29860 165 052527 166 0 6358 167 0 >53000 168B 21 11089 169E 94 19777 170C 22 >53192171 4 11916 172D 104 22084 173 94 25452 174 71 20003 175 1 >53000 176C59 46532 177 0 51738 178 0 >53000 179C 52 22309 180 93 >50359 181E 9927266 182 8 50969 183 0 35204 184 5 43151 185C 94 26547 186 80 16844 18731 18854 188 0 >53000 189D 48 23338 190E 0 25337 191 19 >50905 192 247551 193 2 >53192 194 11 >53192 195 85 23013 196 2 29560 197 0 >53192198 112 45902 199E 18 9517 200B 0 >53192 201 8 >53192 202 1 >53192 203D0 >53192 204 1 >53192 205 12 13110 206 54 20028 207C 16 13158 208D2 >53192 209 51 >53192 210 0 >53192 211C 83 36086 212 69 >53192 213C 1415905 214 8 22180 215 80 19235 216 86 18650 217 92 29562 218 0 >53192219 1 >53192 220B 70 39195 221 1 40533 222B 21 25598 223 76 41755 224 1720360 225 15 23007 226C 0 >53000 227 1 14284 228B 51 23388 229 95 18604230 66 13981 231 79 43226 232 61 18655 233B 5 32173 234 73 15892 23512 >53192 236D 15 25638 237 1 38182 238E 12 16978 239 18 19379 240C 034872 241D 78 25386 242D 97 25477 243 33 >53192 244B 0 16370 245F 7130316 246 1 47945 247 39 26251 248 88 26502 249 100 23353 250 19 18457251 1 >53192 252 18 19227 253 27 >53192 254 91 16562 255 1 >53192 25615 >53192 257 7 >53192 258 8 >53192 259 2 47617 260 54 28136 261 6 21226262G 109 >51193 263 17 >53192 264 24 >53192 265 74 >53192 266C 0 51915267 5 >52894 268 27 27745 269 8 >53192 270C 1 >53192 271B 15 11411 272F92 14257 273 10 29555 274 0 11007 275 53 16906 276 29 16948 277B 9619304 278 121 8534 279G 82 9300 280 0 4177 281C 5 28296 282 0 >53192283C 65 24368 284 50 16234 285G 58 48534 286 0 25178 287E 98 15976 288108 16448 289 2 26418 290 4 11503 291 86 16519 292 1 >53192 293 44 11190294 114 20456 295B 99 >53192 296 96 10826 297 14 23313 298C 61 >53000299D 100 19498 300 0 >53192 301B 0 5652 302 0 16805 303 14 35540 304C 941699 305 0 >53192 306C 10 41624 307 99 26681 308 102 39781 309 9 12000310C 97 >53000 311B 97 14846 312 2 >53192 313 14 >53192 314 3 23595 3150 47185 316 100 21369 317 41 >47618 318 27 >53192 319 70 >52484 320 11012474 321 30 29687 322 10 37130 323 0 >53192 324 31 >53192 325 86 46137326 27 >53192 327 94 >53192 328 0 10002 329 99 14697 330 3 29347 331B 9943107 332B 2 39967 333 2 >53192 334 63 26549 335 3 51148 336 0 >53192337 20 27878 338C 35 >53000 339B 53 19437 340B 32 32752 341 13 26585342C 119 13655 343 62 15548 344 93 17232 345 21 12409 346D 1 39020 347 119378 348 103 14152 349B 94 40798 350 10 28062 351 95 8601 352 16 32910353B 110 12655 354 82 >53000 355 1 9465 356 76 20617 357 0 8824 358 2047446 359 2 25272 360E 55 13132 361 8 >53192 362 23 >53000 363 2 21873364 38 3757 365 86 12470 366 6 >53192 367 20 13404 368 2 47287 3695 >53000 370 33 22663 371 83 7589 372 0 24037 373 0 8142 374 5 >53192375 98 15176 376 2 29126 377 22 18646 378 5 17140 379 112 9237 380 9718292 381 1 24923 382 85 >39934 383 32 15504 384 97 >53192 385 40 >53192386 114 11949 387 61 21235 388 54 >53192 389B 2 >53192 390 99 21565 39160 44809 392 105 19144 393 54 26117 394 14 30759 395 41 11615 396 399999 397 26 >53192 398 2 9831 399 31 12770 400 45 23303 401C 87 9717 40292 24761 403 112 10455 404 0 44624 405 11 21128 406 27 11432 407 10211978 408 88 12745 409 0 >53192 410 103 13729 411 53 8978 412 80 11140413 61 14499 414 39 23433 415 39 38002 416 0 10281 417 8 12778 41819 >53192 419 42 27120 420 110 18698 421 70 10198 422 0 6763 423 14 8455424 78 14163 425 85 15596 426 19 >53000 427 0 32797 428 94 23043 429 5741551 430 31 26293 431 7 6387 432 90 7993 433 16 20821 434 20 12326 4357 13856 436 20 11275 437 3 >53192 438 81 12103 439 −2 21696 440 82 21699441 35 8649 442 79 8876 443I 82 16399 444 23 15522 445 114 10720 44679 >53192 447 0 12969 448 103 >53192 449 94 21114 450 33 19264 451B 137054 452C 4 9069 453 3 >53192 454 1 11111 455 4 >53192 456 0 >53192 45764 >53192 458 90 15703 459 28 14198 460 0 8970 461 25 32036 462J 2 17992463 11 14737 464 119 >53192 465B 3 >53192 466 115 >53192 467 103 >53192468D 14 >53000 469 17 >53192 470 68 20769 471 62 >53192 473 18 14644 47417 9979 475 23 20371 476 30 53182 477 0 21395 478E 0 21514 479 2 26449480 93 27787 481 53 22927 482C 2 51352 483D 19 26191 484 25 27390 485 4322202 486 76 7076 487C 10 9712 488 8 12411 489D 97 20784 490D 87 38047491F 18 7849 492B 2 >53192 493 48 33923 494 17 10354 495 85 15531 496B17 18411 497 67 27052 498F 60 13214 499 22 >53000 500 59 24349 501 1139631 502F 50 3054 503 3 40356 504E 142 12820 505 28 >47368 50632 >53000 507B 22 >45266 508D 96 5132 509 48 24601 510 3 35940 511C 1711777 512C 60 19883 513 63 10682 514 3 >46077 515 0 9461 517E 87 19079518 11 10548 519 65 20324 520 30 >53192 521 0 >53192 522 4 47889 523 2448801 524D 78 8533 525 83 >53192 526 50 10031 527E 66 10638 528 0 >53192529 53 13001 530E 55 15251 531 98 7401 532 9 12162 533E 142 19292 534 299824 535G 9 25309 536I 12 8605 537 2 >53192 538 14 23328 539 10 20785540E −4 >53192 541 37 8152 542 1 33639 543 4 43954 544 75 >53192 545 3715894 546C 15 16774 547 45 13332 548D 54 10129 549 38 10166 550 1 16979551 0 >53192 552 8 11041 553 11 23837 554 63 48909 555C 14 25510 556 8347803 557 73 7859 558B 3 >53192 559D 96 23060 560 112 >53000 561B 829040 562 42 17783 563 62 27019 564 100 10281 565 0 37625 566 3 23700567 11 15782 568 42 11417 569 11 >53000 570 5 >53192 571 2 34848 572B 1136737 573 18 30054 574D 24 52462 575B 14 17450 576B 2 >53192 57720 >53192 578 15 >53192 579D 18 >53192 580F 95 32553 581D 6 10563 582 514430 583 28 23239 584 93 7251 585 58 13736 586 1 >53192 587C 93 22970588 2 21529 589 106 17933 590 13 38595 591 15 14237 592 8 >53192 59352 >53000 594B 12 13423 595 99 12699 596 96 10945 597 89 8650 5983 >53192 599 2 31550 600 9 >53192 601 22 41944

The specific pharmacological responses observed may vary according toand depending on the particular active compound selected or whetherthere are present pharmaceutical carriers, as well as the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith practice of the present invention.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

The invention will now be illustrated by the following non-limitingExamples. The Examples provided herein describe the synthesis ofcompounds of the invention (i.e. compounds of Formula I) as well asintermediates used to prepare compounds of the invention.

Example 1

Synthesis of 3-o-tolylpicolinonitrile (1B)

To a suspension of 3-bromopicolinonitrile (1.0 g, 5.46 mmol), potassiumcarbonate (27 ml, 0.4M in water), o-tolylboronic acid (1A, 0.74 g, 5.46mmol) and tetrakis(triphenylphosphine) palladium (310 mg, 0.27 mmol) inDME (40 ml), was degassed for 20 minutes. The mixture was then heated atreflux. After 2 hours the reaction was filtered through celite and thefiltrate was extracted with EtOAc (30 ml) twice. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The crude product waspurified by flash column (Rf: 0.3 EtOAc/Hexanes=20%). The yield was 94%.MS (m/z) 195 [M+H]⁺

Synthesis of 2-phenyl-1-(3-o-tolylpyridin-2-yl)ethanamine (1C)

To a solution of 3-o-tolylpicolinonitrile (0.5 g, 2.56 mmol) in toluenecooled by an ice bath, benzylmagnesium chloride (2M in THF) (3.0 ml, 6.0mmol) was added dropwise. After 30 minutes, the reaction was warmed upto room temperature and stirring was continued for 1 hr. The reactionwas then cooled to 0° C. and 2-butanol (10 ml) was added. NaBH₄ (187 mg,4.93 mmol) was then added to the solution and the reaction was stirredovernight (warmed up to r.t. slowly). The reaction was quenched withMeOH (3 ml) and extracted with EtOAc (2×30 ml). The organic layer wasdried with Na₂SO₄, filtered and concentrated. The crude product waspurified by flash column. The yield was (180 mg, 0.62 mmol) 24.2%. MS(m/z) 289 [M+H]⁺

Synthesis of2-(6-hydroxy-1H-indol-3-yl)-N-(2-phenyl-1-(3-o-tolylpyridin-2-yl)ethyl)acetamide(1D)

HATU (40 mg, 0.105 mmol) was added to a solution of2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA(0.02 ml, 0.12 mmol) in DMF (0.3 ml). After 10 minutes,2-phenyl-1-(3-o-tolylpyridin-2-yl)ethanamine (29 mg, 0.1 mmol) in 0.2 mlof DMF was added to the reaction. The reaction was stirred for 2 hours.The DMF solution was filtered and purified by RP HPLC to provide thedesired product. The yield was 24 mg. The product is a mixture ofrotamers. The ratio is 3:2. NMR of the major rotamer is reported. ¹H NMR(d-DMSO, 400 MHz) δ 10.22 (s, 1H), 8.6-8.62 (m, 1H), 8.05 (d, 1H), 7.45(d, 1H), 7.34-7.4 (m, 1H), 7.2-7.31 (m, 2H), 7.0-7.18 (m, 5H), 6.88 (s,1H), 6.75 (s, 1H), 6.0-6.64 (m, 2H), 6.5-6.58 (m, 2H), 4.75 (q, 1H),3.3-3.41 (m, 2H), 2.7-2.9 (m, 2H), 1.92 (s, 3H); MS (m/z) 462 [M+H]⁺.

Example 2

Synthesis ofN-(2-phenyl-1-(3-(o-tolyl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(2)

The title compound was prepared according to the method presented forthe synthesis of Compound 1D of Example 1 substituting2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 519 [M+H]⁺.

Example 3

The Synthesis ofN-(2-(3,5-difluorophenyl)-1-(3-o-tolylpyridin-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(3)

The title compound was prepared according to the method presented forthe synthesis of Compound 1D of Example 1 substituting(3,5-difluorobenzyl)magnesium chloride for benzylmagnesium chloride. MS(m/z) 498 [M+H]⁺.

Example 4

The Synthesis ofN-(2-(3,5-difluorophenyl)-1-(3-o-tolylpyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(4)

The title compound was prepared according to the method presented forthe synthesis of Compound 1D of Example 1 substituting(3,5-difluorobenzyl)magnesium chloride for benzylmagnesium chloride and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 555 [M+H]⁺.

Example 5

The Synthesis ofN-(2-(3,5-difluorophenyl)-1-(3-(4-methoxy-2-methylphenyl)pyridin-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(5)

The title compound was prepared according to the method presented forthe synthesis of Compound 1D of Example 1 substituting4-methoxy-2-methylphenylboronic acid for o-tolylboronic acid and(3,5-difluorobenzyl)magnesium chloride for benzylmagnesium chloride toprovide. MS (m/z) 528 [M+H]⁺.

Example 6

The Synthesis ofN-(2-(3,5-difluorophenyl)-1-(3-(4-methoxy-2-methylphenyl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(6)

The title compound was prepared according to the method presented forthe synthesis of Compound 1D of Example 1 substituting4-methoxy-2-methylphenylboronic acid for o-tolylboronic acid,(3,5-difluorobenzyl)magnesium chloride for benzylmagnesium chloride, and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 585 [M+H]⁺.

Example 7

The Synthesis ofN-(2-(3,5-difluorophenyl)-1-(3-(4-methoxy-2,6-dimethylphenyl)pyridin-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(7)

The title compound was prepared according to the method presented forthe synthesis of Compound 1D of Example 1 substituting4-methoxy-2,6-dimethylphenylboronic acid for o-tolylboronic acid and(3,5-difluorobenzyl)magnesium chloride for benzylmagnesium chloride. MS(m/z) 542 [M+H]⁺.

Example 8

The Synthesis ofN-(2-(3,5-difluorophenyl)-1-(3-(4-methoxy-2,6-dimethylphenyl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(8)

The title compound was prepared according to the method presented forthe synthesis of Compound 1D of Example 1 substituting4-methoxy-2,6-dimethylphenylboronic acid for o-tolylboronic acid,(3,5-difluorobenzyl)magnesium chloride for benzylmagnesium chloride, and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 599 [M+H]⁺.

Example 9

Synthesis of 2-(methylthio)-4-o-tolylpyrimidine (9B)

A suspension of 4-bromo-2-(methylthio)pyrimidine (9A, 1.18 g, 7.35mmol), potassium carbonate (37 ml, 0.4 M in water), o-tolylboronic acid(1 g, 7.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (425 mg,0.37 mmol) in DME (40 ml) was degassed for 20 minutes. It was thenheated at reflux for 2 hours. The reaction mixture was cooled andfiltered through celite. The filtrate was extracted with EtOAc (2×30ml). The organic layer was dried with Na₂SO₄, filtered and concentrated.The crude product was purified by flash column (Rf: 0.3 10%EtOAc/Hexanes). The yield was 98%. MS (m/z) 217 [M+H]⁺

Synthesis of 4-o-tolylpyrimidine-2-carbonitrile (9C)

To a solution of 2-(methylthio)-4-o-tolylpyrimidine (1.55 g, 7.2 mmol)in DCM (10 ml) was added mCPBA (77% from Aldrich) (1.25 g, 5.6 mmol).The reaction mixture was stirred for 2 hours then diluted with DCM (50ml) and washed with NaHCO₃(aq) (2×50 ml). The organic layer was driedover Na₂SO₄, filtered and concentrated. The crude product was driedunder high vacuum then redissolved in DMF. KCN(s) (936 mg, 14.4 mmol)was added to the solution and the reaction was stirred overnight. Thereaction was diluted with EtOAc (100 ml) and washed with NaHCO₃(aq)(2×50 ml). The organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by flash column (Rf: 0.3EtOAc/Hexanes=15%). The yield was (690 mg, 3.53 mmol). 49% for twosteps. MS (m/z) 196 [M+H]⁺

Synthesis of 2-phenyl-1-(4-o-tolylpyrimidin-2-yl)ethanamine (9D)

Benzylmagnesium chloride (2M in THF) (2.11 ml, 4.22 mmol) was addeddropwise to a solution of 4-o-tolylpyrimidine-2-carbonitrile (9 C, 690mg, 3.52 mmol) in toluene (10 ml) at 0° C. After 30 minutes, thereaction was warmed up to r.t. and stirred for 1 hr. The reaction wasthen cooled it to 0° C. and 2-butanol (10 ml) was added followed byNaBH₄(s) (187 mg, 4.93 mmol). The reaction mixture was stirred overnightat room temperature. The reaction was quenched with MeOH (3 ml) andextracted with EtOAc (2×30 ml). The organic layer was dried with Na₂SO₄,filtered and concentrated. The crude product was purified by flashcolumn (Rf: 0.4 10% MeOH/DCM). The yield was 380. MS (m/z) 290 [M+H]⁺

Synthesis of2-(5-hydroxy-1H-indol-3-yl)-N-(2-phenyl-1-(4-o-tolylpyrimidin-2-yl)ethyl)acetamide(9E)

HATU (40 mg, 0.105 mmol) was added to a solution of2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIEPA(0.02 ml, 0.12 mmol) in DMF (0.3 ml). After 10 minutes,2-phenyl-1-(4-o-tolylpyrimidin-2-yl)ethanamine (29 mg, 0.1 mmol) in 0.2ml of DMF was added to the reaction. The reaction was stirred for 2hours. The DMF solution was filtered and purified by RP HPLC using a C18column and a gradient of 20% B to 85% B over 25 minutes (A=0.1% TFA/H₂O,B=0.1% TFA/acetonitrile) to provide the title compound. The yield was 30mg. ¹H NMR (d-DMSO, 400 MHz) δ 10.48 (s, 1H), 8.79 (d, 1H), 8.14 (d,1H), 7.5 (d, 1H), 7.22-7.3 (m, 4H), 7.08-7.35 (m, 4H), 6.92-6.98 (m,3H), 6.6 (s, 1H), 6.58 (d, 1H), 5.21 (q, 1H), 3.4-3.55 (m, 2H), 3.0-3.2(m, 2H), 1.98 (s, 3H); MS (m/z) 463 [M+H]⁺

Example 10

The Synthesis ofN-(2-phenyl-1-(4-o-tolylpyrimidin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(10)

The title compound was prepared according to the method presented in thesynthesis of Example 9 substituting2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 520 [M+H]⁺.

Examples 11

The Synthesis ofN-(2-(3,5-difluorophenyl)-1-(4-o-tolylpyrimidin-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(11)

The title compound was prepared according to the method presented in thesynthesis of Example 9 substituting (3,5-difluorobenzyl)magnesiumchloride for benzylmagnesium chloride. MS (m/z) 499 [M+H]⁺.

Example 12

The Synthesis ofN-(2-(3,5-difluorophenyl)-1-(4-o-tolylpyrimidin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(12)

The title compound was prepared according to the method presented in thesynthesis of Example 9 substituting (3,5-difluorobenzyl)magnesiumchloride for benzylmagnesium chloride and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 556 [M+H]⁺.

Example 13

Synthesis of 3-(4-methoxyphenyl)picolinaldehyde (13B)

A suspension of 3-bromopicolinaldehyde (13A, 1.86 g, 10 mmol), potassiumcarbonate (50 ml, 2M in water), 4-methoxyphenylboronic acid (1.6 g, 10.5mmol) and tetrakis(triphenylphosphine) palladium (580 mg, 0.5 mmol) inDME (70 ml) was degassed for 30 minutes. The mixture was heated atreflux for 2 hours. The reaction was cooled and filtered through celite.The filtrate was extracted with EtOAc (2×50 ml). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The crude product waspurified by flash column (Rf: 0.4 50% EtOAc/Hexanes). The yield was 2 g.MS (m/z) 214 [M+H]⁺

Synthesis of(S)—N-((3-(4-methoxyphenyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(13C)

Copper(II) sulfate (anhydrous 2.52 g, 17.2 mmol) was added to a solutionof 3-(4-methoxyphenyl)picolinaldehyde (1.7 g, 8.6 mmol) and(S)-2-methylpropane-2-sulfinamide (1.06 g, 9.4 mmol) in DCM (20 ml). Thesuspension was stirred overnight at room temperature. The reaction wasfiltered and washed with DCM (3×20 ml). The filtrate was concentrated.The crude product was purified by flash column (Rf: 0.6, 60%EtOAc/Hexanes). The yield was (2.4 g, 7.7 mmol) 90%. MS (m/z) 195 [M+H]⁺

Synthesis of(S)—N—((R)-2-(3,5-difluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide(13D) and(S)—N—((S)-2-(3,5-difluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide(13E)

(3,5-difluorobenzyl)magnesium bromide (0.25 M in ether, 10 ml, 2.5 mmol)was added dropwise to a solution of(S)—N-((3-(4-methoxyphenyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(13C, 0.5 g, 1.67 mmol) in DCM (40 ml) at −78° C. The reaction wasstirred for 3 hour at −78° C. Ammonium chloride (aq, 10 ml) was added tothe reaction and the mixture was allowed to warm to r.t. The mixture wasextracted with EtOAc (2×30 ml). The organic layer was dried over Na₂SO₄,filtered and concentrated. The crude product contained a mixture ofdiastereomers 13D ((S,R) sulfinamide intermediate) and 13E ((S,S)sulfinamide intermediate) separable by flash chromatography (Rf: 0.3 50%EtOAc/Hexanes). The yield was (220 mg, 30%). MS (m/z) 445 [M+H]⁺

(S)-2-(3,5-difluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethanaminehydrochloride salt (13F)

(S)—N—((S)-2-(3,5-difluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide(13E, 220 mg, 0.5 mmol) was treated with a mixture of 2 ml of 1.25 M HClin MeOH/1 ml of 4 M HCl in dioxane for 1 hour. The solvent was removedin vacuo. Used without further purification. MS (m/z) 341 [M+H]⁺

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(13G)

HATU (40 mg, 0.105 mmol) was added to a solution of2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA(0.04 ml, 0.24 mmol) in DMF (0.3 ml). After 10 minutes,(S)-2-(3,5-difluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethanaminehydrochloride salt (34 mg, 0.1 mmol) in 0.2 ml of DMF was added. Thereaction was stirred for 2 hours at room temperature. The DMF solutionwas filtered and purified by RP HPLC using a C18 column and a gradientof 20% B to 85% B over 25 minutes (A=0.1% TFA/H₂O, B=0.1%TFA/acetonitrile) to provide the desired product. The yield was 39 mg.¹H NMR (d-DMSO, 400 MHz) δ 10.22 (s, 1H), 8.6 (d, 1H), 8.4 (d, 1H), 7.53(d, 1H), 7.3-7.4 (m, 1H), 7.0-7.1 (m, 3H), 6.8-6.98 (m, 4H), 6.78 (s,1H), 6.56 (d, 1H), 6.3-6.4 (m, 2H), 5.21 (q, 1H), 3.75 (s, 3H), 3.4 (s,2H), 2.9 (d, 2H); MS (m/z) 514 [M+H]⁺

Example 14

The Synthesis of(S)-2-(5-hydroxy-1H-indol-3-yl)-N-(2-phenyl-1-(3-o-tolylpyridin-2-yl)ethyl)acetamide(14)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting o-tolylboronic acid for4-methoxyphenylboronic acid and benzylmagnesium chloride for(3,5-difluorobenzyl)magnesium chloride. MS (m/z) 462 [M+H]⁺.

Example 15

The Synthesis of(R)-2-(5-hydroxy-1H-indol-3-yl)-N-(2-phenyl-1-(3-o-tolylpyridin-2-yl)ethyl)acetamide(15)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting o-tolylboronic acid for4-methoxyphenylboronic acid and benzylmagnesium chloride for(3,5-difluorobenzyl)magnesium chloride and carrying forward the (S,R)sulfinamide intermediate. MS (m/z) 462 [M+H]⁺.

Example 16

The Synthesis of(R)—N-(2-phenyl-1-(3-o-tolylpyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(16)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting o-tolylboronic acid for4-methoxyphenylboronic acid, benzylmagnesium chloride for(3,5-difluorobenzyl)magnesium chloride,2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid and carrying forward the(S,R) sulfinamide intermediate. MS (m/z) 519 [M+H]⁺.

Example 17

The Synthesis of(S)—N-(2-phenyl-1-(3-o-tolylpyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(17)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting o-tolylboronic acid for4-methoxyphenylboronic acid, benzylmagnesium chloride for(3,5-difluorobenzyl)magnesium chloride, and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 519 [M+H]⁺.

Example 18

The Synthesis of(R)—N-(1-(3-(4-methoxy-2-methylphenyl)pyridin-2-yl)-2-phenylethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(18)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting 4-methoxy-2-methylphenylboronicacid for 4-methoxyphenylboronic acid, benzylmagnesium chloride for(3,5-difluorobenzyl)magnesium chloride,2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid and carrying forward the(S,R) sulfinamide intermediate. MS (m/z) 549 [M+H]⁺.

Example 19

The Synthesis of(S)—N-(1-(3-(4-methoxy-2-methylphenyl)pyridin-2-yl)-2-phenylethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(19)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting 4-methoxy-2-methylphenylboronicacid for 4-methoxyphenylboronic acid, benzylmagnesium chloride for(3,5-difluorobenzyl)magnesium chloride, and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 549 [M+H]⁺.

Example 20

The Synthesis of(S)-2-(5-hydroxy-1H-indol-3-yl)-N-(1-(3-(4-methoxyphenyl)pyridin-2-yl)-2-phenylethyl)acetamide(20)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting benzylmagnesium chloride for(3,5-difluorobenzyl)magnesium chloride. MS (m/z) 478 [M+H]⁺.

Example 21

The Synthesis of(S)—N-(1-(3-(4-methoxyphenyl)pyridin-2-yl)-2-phenylethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(21)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting benzylmagnesium chloride for(3,5-difluorobenzyl)magnesium chloride, and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 535 [M+H]⁺.

Example 22

The Synthesis of(R)-2-(5-hydroxy-1H-indol-3-yl)-N-(1-(3-(4-methoxyphenyl)pyridin-2-yl)-2-phenylethyl)acetamide(22)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting benzylmagnesium chloride for(3,5-difluorobenzyl)magnesium chloride and carrying forward the (S,R)sulfinamide intermediate. MS (m/z) 478 [M+H]⁺.

Example 23

The Synthesis of(R)—N-(1-(3-(4-methoxyphenyl)pyridin-2-yl)-2-phenylethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(23)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting benzylmagnesium chloride for(3,5-difluorobenzyl)magnesium chloride,2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid and carrying forward the(S,R) sulfinamide intermediate. MS (m/z) 535 [M+H]⁺.

Example 24

The Synthesis of(S)—N-(2-(3-fluorophenyl)-1-(3-o-tolylpyridin-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(24)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting o-tolylboronic acid for4-methoxyphenylboronic acid and (3-fluorobenzyl)magnesium chloride for(3,5-difluorobenzyl)magnesium chloride. MS (m/z) 480 [M+H]⁺.

Example 25

The Synthesis of(S)—N-(2-(3-fluorophenyl)-1-(3-o-tolylpyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(25)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting o-tolylboronic acid for4-methoxyphenylboronic acid, (3-fluorobenzyl)magnesium chloride for(3,5-difluorobenzyl)magnesium chloride, and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 537 [M+H]⁺.

Example 26

The Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-o-tolylpyridin-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(26)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting o-tolylboronic acid for4-methoxyphenylboronic acid. MS (m/z) 498 [M+H]⁺.

Example 27

The Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-o-tolylpyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(27)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting o-tolylboronic acid for4-methoxyphenylboronic acid and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 555 [M+H]⁺.

Example 28

The Synthesis of(S)—N-(2-(3-fluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(28)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting (3-fluorobenzyl)magnesium chloridefor (3,5-difluorobenzyl)magnesium chloride. MS (m/z) 496 [M+H]⁺.

Example 29

The Synthesis of(S)—N-(2-(3-fluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(29)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting (3-fluorobenzyl)magnesium chloridefor (3,5-difluorobenzyl)magnesium chloride, and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 553 [M+H]⁺.

Example 30

The Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(30)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 571 [M+H]⁺.

Example 31

The Synthesis of(S)—N-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(1H-indol-3-yl)acetamide(31)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting 4-chlorophenylboronic acid for4-methoxyphenylboronic acid and 2-(1H-indol-3-yl)acetic acid for2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 502 [M+H]⁺.

Example 32

The Synthesis of(S)—N-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(32)

The title compound was prepared according to the method presented forthe synthesis of Example 19 substituting 4-chlorophenylboronic acid for4-methoxyphenylboronic acid. MS (m/z) 518 [M+H]⁺.

Example 33

The Synthesisof(S)—N-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(33)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting 4-chlorophenylboronic acid for4-methoxyphenylboronic acid and 2-(5-fluoro-1H-indol-3-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 502 [M+H]⁺.

Example 34

Synthesis of methyl2-(5-(benzyloxy)-6-methoxy-1H-indol-3-yl)-2-oxoacetate (34B)

A round bottom flask was charged with ether (3 ml) and5-(benzyloxy)-6-methoxy-1H-indole (34A, 1 g, 3.9 mmol) followed by slowaddition of oxalyl chloride (0.34 ml, 3.9 mmol). The reaction wasstirred for one minute after complete addition of all reagents thenquickly filtered. The cake was soaked in 1 ml methanol after which themethanol was filtered off. This was repeated three times to give a 1200mg of greenish/yellow colored solid which was used with no furtherpurification. The yield was 82%. MS (m/z) 339.9 [M+H]⁺.

Synthesis of methyl 2-(5-(benzyloxy)-6-methoxy-1H-indol-3-yl)acetate(34C)

A round bottom is charged with methyl2-(5-(benzyloxy)-6-methoxy-1H-indol-3-yl)-2-oxoacetate (34B, 1200 mg,3.2 mmol), dioxane (100 ml), Pd/C (300 mg), H₂NaO₂P.H₂O (3 mg, 28 mmol),and H₂O (40 ml). The resulting mixture was stirred at 95° C. until doneas indicated by LC/MS. The reaction mixture was cooled to RT andfiltered over a plug of celite, rinsing with ethyl acetate. The layerswere partitioned and the organic layer was dried over sodium sulfate,filtered and concentrated to give a solid mixture of benzyl andde-benzylated solid which was used with no further purification. MS(m/z) 325.98 [M+H]⁺.

Synthesis of 2-(5-(benzyloxy)-6-methoxy-1H-indol-3-yl)acetic acid (34D)

A round bottom flask was charged with methyl2-(5-(benzyloxy)-6-methoxy-1H-indol-3-yl)acetate (34C, 140 mg, mixtureof benzyl and non benzyl), methanol (1 mil), and THF (1 ml). To theresulting mixture was added a solution of LiOH (60 mg, 2.5 mmol)dissolved in water (1 ml). The mixture was stirred until done afterwhich the mixture was diluted with ethyl acetate and the layersseparated, the aqueous layer was acidified and extracted 2× with ethylacetate and the combined organic layers were dried over sodium sulfate,filtered and concentrated to give mixture of both benzyl and non-benzylproducts as a solid which was used with no further purification. MS(m/z) 311.92 [M+H]⁺

Synthesis of(S)-2-(5-(benzyloxy)-6-methoxy-1H-indol-3-yl)-N-(2-(3,5-difluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethyl)acetamide(34E)

A round bottom flask was charged with2-(5-(benzyloxy)-6-methoxy-1H-indol-3-yl)acetic acid (66 mg, mixture ofbenzyl and non-benzyl), DMF (2 ml), N-methyl-morpholine (0.1 ml, 0.9mmol), HATU (50 mg, 0.13 mmol), and(S)-2-(3,5-difluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethanamine(34 mg, 0.1 mmol). The mixture was stirred until done as indicated byLC/MS then filtered and purified by HPLC to afford the desired product(3.2 mg, ¹H NMR ((CD₃)₂SO, 300 MHz) δ 10.50 (s, 1H), 8.53 (dd, 1H), 8.37(d, 1H), 7.47 (dd, 1H), 7.41 (d, 2H), 7.35 (t, 2H), 7.30-7.27 (m, 2H),7.11 (s, 1H), 7.07 (d, 2H), 6.88-6.85 (m, 5H), 6.33 (d, 2H), 5.25 (q,1H), 4.89 (s, 2H), 3.74 (s, 3H), 3.39 (s, 2H), 2.88 (d, 2H), 2.78 (s,3H); MS (m/z) 634.4 [M+H]⁺.

Example 35

The Synthesis of methyl2-(5-(tert-butoxycarbonylamino)-1H-indol-3-yl)-2-oxoacetatehydrochloride (35B)

The title compound was prepared according to the method presented in thesynthesis of methyl2-(5-(benzyloxy)-6-methoxy-1H-indol-3-yl)-2-oxoacetate. Treatment oftert-butyl 1H-indol-5-ylcarbamate (10.8 mmol) occurred under the sameconditions, adjusted for scale, to afford the desired compound. Theyield was 76% as HCl salt. MS (m/z) 319.0 [M+H]⁺

The Synthesis of methyl2-(5-(tert-butoxycarbonylamino)-1H-indol-3-yl)acetate (35C)

The title compound was prepared according to the method presented in thesynthesis of methyl 2-(5-(benzyloxy)-6-methoxy-1H-indol-3-yl)acetate.Treatment of methyl2-(5-(tert-butoxycarbonylamino)-1H-indol-3-yl)-2-oxoacetate (7.0 mmol)occurred under the same conditions, adjusted for scale, to afford thedesired product. The yield was 69%. MS (m/z) 249.15 [M+H-t-Butyl]⁺

Synthesis of methyl 2-(5-amino-1H-indol-3-yl)acetate (35D)

A round bottom flask was charged with methyl2-(5-(tert-butoxycarbonylamino)-1H-indol-3-yl)acetate (1.35 g, 4.4 mmol)and TFA (4 ml). The mixture was stirred until done after which themixture was concentrated to a light pink oil. The oil was diluted withDCM, sonicated, and filtered to give 1660 mg of white solid which wasused with no further purification. The yield was 76%. MS (m/z) 205.15[M+H]⁺

Synthesis of methyl 2-(5-(methylsulfonamido)-1H-indol-3-yl)acetate (35E)

A round bottom flask was charged with methyl2-(5-amino-1H-indol-3-yl)acetate (200 mg, 1 mmol), DCM (3 ml), and TEA(0.43 ml, 3.1 mmol) and cooled to 0° C. To the resulting mixture MsCl(0.04 ml, 0.5 mmol) dissolved in DCM (2 ml) was added drop wise. Themixture was stirred until done after which the mixture was washed with asolution of 10% aqueous citric acid followed by a saturated solution ofNaHCO₃. The organic layer was dried over sodium sulfate, concentrated byflash chromatography to give 80 mg of solid. The yield was 29%. MS (m/z)282.9 [M+H]⁺.

The Synthesis of 2-(5-(methylsulfonamido)-1H-indol-3-yl)acetic acid(35F)

The title compound was prepared according to the method presented in thesynthesis of 2-(5-(benzyloxy)-6-methoxy-1H-indol-3-yl)acetic acid.Treatment of methyl 2-(5-(methylsulfonamido)-1H-indol-3-yl)acetate (0.28mmol) occurred under the same conditions, adjusted for scale, to affordthe desired product. The yield was 95%. MS (m/z) 268.8 [M+H]⁺.

The Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethyl)-2-(5-(methylsulfonamido)-1H-indol-3-yl)acetamide(35G)

The title compound was prepared according to the method presented in thesynthesis of(S)-2-(5-(benzyloxy)-6-methoxy-1H-indol-3-yl)-N-(2-(3,5-difluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethyl)acetamide.Treatment of 2-(5-(methylsulfonamido)-1H-indol-3-yl)acetic acid (0.14mmol) occurred under the same conditions, adjusted for scale, to affordthe desired product. The mixture was stirred until done by LC/MS thenfiltered and purified by HPLC to afford the desired product (3.7 mg,4%): ¹H NMR ((CD₃)₂SO, 300 MHz) δ 10.84 (s, 1H), 9.15 (s, 1H), 8.58 (dd,1H), 8.42 (d, 1H), 7.48 (dd, 1H), 7.36-7.35 (m, 1H), 7.32 (dd, 1H), 7.25(d, 1H), 7.07 (s, 1H), 7.05 (d, 2H), 6.92 (dd, 1H), 6.87 (d, 3H), 6.32(d, 2H), 5.24 (q, 1H), 3.74 (s, 3H), 3.47 (s, 2H), 2.89 (d, 2H), 2.78(s, 3H); MS (m/z) 591.37 [M+H]⁺.

Examples 36

Synthesis of methyl3,3,3-trifluoro-2-(5-fluoro-1H-indol-3-yl)-2-hydroxypropanoate (36B)

A round bottom flask was charged with 5-fluoro-1H-indole (3000 mg, 22.2mmol) and methyl 3,3,3-trifluoro-2-oxopropanoate (2.27 ml, 22.2 mmol).The mixture was stirred until done and then diluted with DMF (100 ml),cool to 0° C. and slowly add SOCl₂ (4 ml, 55.5 mmol) until peak hasshifted by LC/MS. Slowly add NaBH₄ (2800 mg, 66.6 mmol) in portions andallow mixture to stir for 3 hours after which the mixture was dumpedinto stirring saturated NH₄Cl and resulting solids were filtered off andthe mother liquor was extracted 2× ethyl acetate. The organic layer wasdried over sodium sulfate and concentrated and purified by flashchromatography to yield 2.98 g of the desired compound in a yield of49%. MS (m/z) 275.9 [M+H]⁺.

Synthesis of 3,3,3-trifluoro-2-(5-fluoro-1H-indol-3-yl)propanoic acid(36C)

A round bottom flask was charged with methyl3,3,3-trifluoro-2-(5-fluoro-1H-indol-3-yl)-2-hydroxypropanoate (1000 mg,3.6 mmol), HCl (4 ml), and THF (2 ml). The mixture was stirred at 95° C.for 3 days and then the cooled solution was extracted with ethylacetate, the organic layer was extracted with saturated NaHCO₃, theaqueous layer was acidified and extract 2× with ethyl acetate and thecombined organic layers were dried over sodium sulfate and concentratedto give 210 mg of solid which was used with no further purification. Theyield was 22%. MS (m/z) 262.1 [M+H]⁺.

Synthesis of (S)-tert-butyl1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(36D)

A round bottom flask was charged with 50A (1 g, 2.4 mmol), DME (40 ml),4-chlorophenylboronic acid (454 mg, 3 mmol), Pd(PPh₃)₄ (280 mg, 0.24mmol) and K₂CO₃ (669 mg, 4.8 mmol) dissolved in water (5 ml). Themixture was heated overnight at 85° C. Allow the reaction to cool thendilute with H₂O and extract 2× EtOAc. The combined organic layers werewashed with brine then dried over sodium sulfate, concentrated, andpurified by flash chromatography to give 692 mg of desired compound. Theyield was 64%. MS (m/z) 445.3 [M+H]⁺.

Synthesis of(S)-1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethanaminetrifluoroacetate (36E)

A round bottom flask was charged with (S)-tert-butyl1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(690 mg, 1.6 mmol) and TFA:DCM 1:2.5 (7 ml). The reaction was stirred atroom temperature until done by LC/MS then concentrated 2× from DCM. Thecrude solid was used as is in next reaction. MS (m/z) 345.3 [M+H]⁺.

Synthesis of CompoundsN—((S)-1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-3,3,3-trifluoro-2-(5-fluoro-1H-indol-3-yl)propanamide(36F and 36G)

A 2 dram vial was charged with 36C (200 mg, 0.8 mmol), 36E (240 mg, 0.7mmol), HATU (351 mg, 0.9 mmol), NMM (0.1 ml, 0.6 mmol) and DMF (6 ml).The mixture was stirred until done by LC/MS then diluted with a 1:1mixture of TFA:water (0.5 ml), filtered and purified by HPLC to affordthe separated diastereomeric products (36F, 52.9 mg, 12%; 36G, 166.1 mg,37%): 36F ¹H NMR ((CD₃)₂SO, 300 MHz) δ 11.27 (s, 1H), 8.98 (dd, 1H),8.67 (dd, 1H), 7.59 (dd, 1H), 7.47 (d, 2H), 7.41 (dd, 1H), 7.35-7.31 (m,3H), 7.21 (d, 2H), 6.90 (dt, 1H), 6.69 (dt, 1H), 6.21 (d, 2H), 5.17 (q,1H), 4.95 (q, 1H), 2.83 (m, 2H); MS (m/z) 588.6 [M+H]⁺. 36G ¹H NMR((CD₃)₂SO, 300 MHz) δ 11.27 (s, 1H), 8.98 (dd, 1H), 8.51 (dd, 1H), 7.50(dd, 1H), 7.38-7.28 (m, 6H), 7.05 (d, 2H), 6.96 (dt, 1H), 6.90 (dt, 1H),6.50 (d, 2H), 5.15 (q, 1H), 4.90 (q, 1H), 3.00-2.98 (m, 2H); MS (m/z)588.6 [M+H]⁺.

Example 37

The Synthesis of(S)—N-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide(37)

The title compound was prepared according to the method presented in thesynthesis of Example 13 substituting 4-chlorophenylboronic acid for4-methoxyphenylboronic acid and2-(5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid for2-(5-hydroxy-1H-indol-3-yl)acetic acid. MS (m/z) 519 [M+H]⁺.

Example 38

Synthesis of(S)—N-((3-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(38B)

The title compound was prepared according to the procedure described inthe synthesis of 13C in Example 13 utilizing 3-bromopicolinaldehyde. MS(m/z) 288.9 [M+H]⁺

Synthesis of(S)—N—((S)-1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(38C)

The title compound was prepared according to the procedure described inthe synthesis of 13E in Example 13 utilizing 38B. MS (m/z) 417.1 [M+H]⁺.

Synthesis of(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(38D)

A solution of(S)—N—((S)-1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(1 g, 2.4 mmol) in 6 ml of HCl (2N/4 ml of MeOH and 2 ml of 1,4-dioxane)was stirred for 3 hours. The solvent was removed and the crude productwas dried by high vacuum. Used without further purification. To asolution of 2-(5-hydroxy-1H-indol-3-yl)acetic acid (304 mg, 1.58 mmol)and DIEA (0.6 ml, 3.32 mmol) in DMF (5 ml), was added HATU (630 mg, 1.66mmol). After 20 minutes, the crude product from last step in 5 ml of DMFwas added to the solution. It was stirred for 2 hours. The DMF solutionwas removed. Redissolved in 100 ml of EtOAc and washed with NaHCO₃ (aq)and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. Purified the crude product by flash column (Rf: 0.3MeOH/DCM=5%). The yield was (486 mg, 1.15 mmol). 48% for two steps. ¹HNMR (d-CD₃OD, 400 MHz) δ 8.36 (d, 1H), 7.9 (d, 1H), 7.11-7.17 (m, 2H),7.035 (s, 1H), 6.8 (s, 1H), 6.6-6.7 (m, 2H), 6.51-6.53 (m, 2H), 5.73 (t,1H), 3.57 (s, 2H), 3.0-3.1 (m, 1H), 2.9-39 (m, 1H); MS (m/z) 486 [M+H]⁺.

Synthesis of(S)—N-(1-(3-(3-cyanophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(38E)

A mixture of(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(48.7 mg, 0.1 mmol), potassium carbonate (27 mg, 0.2 mmol) in 0.5 ml ofwater, tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.007 mmol) and3-cyanophenylboronic acid (0.12 mmol) in DME (1.5 mL) was heated at 120°C. for 30 minutes under microwave irradiation. Solvents wereconcentrated in vacuo and the residue was purified by RP HPLC using aC18 column to provide the title product: ¹H NMR (d-DMSO, 400 MHz) δ10.46 (s, 1H), 8.68 (d, 1H), 8.53 (d, 1H), 7.81 (d, 1H), 7.51-7.55 (m,4H), 7.46 (s, 1H), 7.36-7.38 (m, 1H), 7.05 (s, 1H), 6.89-6.94 (m, 2H),6.8 (s, 1H), 6.53 (d, 1H), 6.34 (d, 1H), 5.09 (q, 1H), 3.41 (q, 2H),2.8-3.0 (m, 2H); MS (m/z) 509 [M+H]⁺.

Example 39

The Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(39)

The title compound was prepared according to the method presented in thesynthesis of Example 38 substituting 3-carbamoylphenylboronic acid for3-cyanophenylboronic acid. MS (m/z) 527 [M+H]⁺.

Example 40

The Synthesis of(S)-2-chloro-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(40)

The title compound was prepared according to the method presented in thesynthesis of Example 38 substituting 3-carbamoyl-4-chlorophenylboronicacid for 3-cyanophenylboronic acid. MS (m/z) 561 [M+H]⁺.

Example 41

The Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(41)

The title compound was prepared according to the method presented in thesynthesis of Example 38 substituting 3-carbamoyl-4-fluorophenylboronicacid for 3-cyanophenylboronic acid. MS (m/z) 545 [M+H]⁺.

Example 42

The Synthesis of(S)-4-(2-(2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(42)

The title compound was prepared according to the method presented in thesynthesis of Example 38 substituting 4-carbamoylphenylboronic acid for3-cyanophenylboronic acid. MS (m/z) 527 [M+H]⁺.

Example 43

The Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-sulfamoylphenyl)pyridin-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(43)

The title compound was prepared according to the method presented in thesynthesis of Example 38 substituting 4-sulfamoylphenylboronic acid for3-cyanophenylboronic acid. MS (m/z) 563 [M+H]⁺.

Example 44

The Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(3-sulfamoylphenyl)pyridin-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(44)

The title compound was prepared according to the method presented in thesynthesis of Example 38 substituting 3-sulfamoylphenylboronic acid for3-cyanophenylboronic acid. MS (m/z) 563 [M+H]⁺.

Example 45

The Synthesisof(S)-4-(2-(2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)-N-methylbenzamide(45)

The title compound was prepared according to the method presented in thesynthesis of Example 38 substituting 4-(methylcarbamoyl)phenylboronicacid for 3-cyanophenylboronic acid. MS (m/z) 540 [M+H]⁺.

Example 46

The Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)-N-methylbenzamide(46)

The title compound was prepared according to the method presented in thesynthesis of Example 38 substituting 3-(methylcarbamoyl)phenylboronicacid for 3-cyanophenylboronic acid. MS (m/z) 540 [M+H]⁺.

Example 47

The Synthesis of(S)-4-(2-(2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)-N,N-dimethylbenzamide(47)

The title compound was prepared according to the method presented in thesynthesis of Example 38 substituting 4-(dimethylcarbamoyl)phenylboronicacid for 3-cyanophenylboronic acid. MS (m/z) 555 [M+H]⁺.

Example 48

The Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)-N,N-dimethylbenzamide(48)

The title compound was prepared according to the method presented in thesynthesis of Example 38 substituting 3-(dimethylcarbamoyl)phenylboronicacid for 3-cyanophenylboronic acid. MS (m/z) 555 [M+H]⁺.

Example 49

The Synthesis ofS)—N-(1-(3-(3-(1H-tetrazol-5-yl)phenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(49)

To a solution of(S)—N-(1-(3-(3-cyanophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(10 mg, 0.02 mmol) in a mixture of 1 mL isopropanol and 1 mL water in a5 mL microwave tube was added ZnBr₂ (4.5 mg, 0.02 mmol) and NaN₃ (2.6mg, 0.04 mmol) at room temperature. The tube was sealed and the mixturewas heated at 100° C. overnight. After the completion of the reaction,the mixture was purified by reverse phase HPLC to afford the desiredproduct (3.4 mg, 0.006 mmol); MS (m/z): 552.1 [M+H]⁺.

Example 50

Synthesis of(S)-tert-butyl1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (50A)

Mixed 1.5M HCl/MeOH (2 ml) and 4N HCl/1,4-dioxane (1.0 ml) together.Added the resulting solution to theN—((S)-1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(1.02 g, 2.44 mmol). After 10 min, concentrated reaction mixture invacuo. Co-evaporated residue with Et₂O until material became a solid.Collected solid by filtration. Suspended solids (702 mg, 2.01 mmol) inCH₂Cl₂. Di-tert-butyl dicarbonate (482 mg, 2.21 mmol) was added to thesuspension followed by triethylamine (560 μl, 4.02 mmol). Stirredreaction at room temperature for 30 min. Concentrated reaction in vacuo.Partitioned residue between EtOAc and H₂O. Extracted aqueous layer 2×with EtOAc. Washed combined organics with brine. Dried organics overMgSO₄, filtered and concentrated. Purified residue on 40 g SiO₂ columnusing EtOAc/hex (rf=0.47 in 20% EtOAc/hex.). Combined pure fractions andconcentrated. Dried solid on high vacuum for 3 hrs. The yield was 736mg.

Synthesis of (S)-tert-butyl1-(3-(3-carbamoylphenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(50B)

Dissolved (S)-tert-butyl1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate (736 mg,1.78 mmol) and 3-carbamoylphenylboronic (352 mg, 2.14 mmol) in1,2-dimethoxyethane. Added 0.4N aq. K₂CO₃ (515 μl, 3.56 mmol) anddegassed reaction by evacuation and purge with N₂ (3×). Added Pd(PPh₃)₄(206 mg, 0.178 mmol) and degassed again. Heated reaction at 80° C.overnight. LC/MS of reaction mixture shows complete conversion toproduct. Filtered cooled reaction mixture through celite, washing withEtOAc. Partitioned filtrate between EtOAc and H₂O. Extracted aqueouslayer 2× with EtOAc. Washed combined organics with brine. Dried organicsover MgSO₄, filtered and concentrated. Purified residue on 40 g SiO₂column using EtOAc/hex (rf=0.25 in 50% EtOAc/hex.) Combined purefractions and concentrated. Dried solid on high vacuum for 3 hrs. Theyield was 750 mg. ¹H NMR (400 MHz, CDCl₃) δ 8.64 (dd, J=4.7, 1.5 Hz,1H), 7.96 (d, J=7.7 Hz, 1H), 7.72 (s, 2H), 7.43 (dd, J=16.4, 8.6 Hz,2H), 7.24 (s, 1H), 6.83 (d, J=7.4 Hz, 1H), 6.50 (t, J=9.0 Hz, 1H), 6.06(d, J=6.2 Hz, 2H), 5.79 (s, 1H), 5.67 (s, 1H), 5.39 (m, 1H), 2.93 (m,2H), 1.42 (s, 9H).

Synthesis of(S)-3-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamidetrifluoroacetate (50C)

(S)-tert-butyl1-(3-(3-carbamoylphenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(750 mg, 1.65 mmol) was dissolved in 5 ml CH₂Cl₂. To the solution wasadded 5 ml of trifluoroacetic acid. The reaction was stirred at roomtemperature for 30 min. Concentrated reaction mixture in vacuo. Driedresulting solid on high vacuum overnight. The yield was 759 mg.

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(5-fluoro-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(50D)

Combined(S)-3-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamidetrifluoroacetate (133 mg, 0.285 mmol) 2-(5-fluoro-1H-indol-3-yl)aceticacid (50 mg, 0.259 mmol), and HATU (108 mg, 0.285 mmol) in 20 ml vial.Added DMF and stirred to dissolve the solids. Addeddiisopropylethylamine (135 μl, 0.77 mmol) and stirred reaction at roomtemperature for 90 min. Purified reaction mixture on prep reverse phaseHPLC using 20-80% B (A=0.1% TFA/H₂O; B=0.1% TFA/ACN). Combined purefractions as determined by LC/MS and lyophilized. The yield was 98 mg.¹H NMR (400 MHz, d-DMSO) δ 10.89 (s, 1H), 8.66 (m, 2H), 7.95 (s, 1H),7.86 (d, 1H), 7.73 (s, 1H), 7.62 (dd, 1H), 7.44 (m, 4H), 7.22 (dd, 1H),7.10 (m, 2H), 6.84 (m, 2H), 6.47 (d, 2H), 5.73 (broad), 5.19 (m, 1H),3.44 (d, 2H), 2.94 (m, 2H); MS (m/z) 529 [M+H]⁺.

Example 51

The Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(51)

The title compound was prepared according to the method presented forthe synthesis of Example 50 substituting2-(5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid for2-(5-fluoro-1H-indol-3-yl)acetic acid. MS (m/z) 528 [M+H]⁺.

Example 52

The Synthesis of 3-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(7-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(52)

The title compound was prepared according to the method presented forthe synthesis of Example 50 substituting2-(7-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid for 2-(5-fluoro-1H-indol-3-yl)acetic acid. MS (m/z) 598 [M+H]⁺.

Example 53

Synthesis of(S)—N-(1-(3-(cyclopropylethynyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(53)

To a solution of(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(97.4 mg, 0.2 mmol), bis(triphenylphosphine)dichloro palladium (15 mg,0.021 mmol), copper(I) iodide (4 mg, o.o21 mmol) in DMF (0.36 ml) andtriethylamine (0.6 ml), ethynylcyclopropane (20.8 mg, 0.315 mmol) wasadded to the solution. It was heated at 120° C. for 120 minutes undermicrowave irradiation. Solvents were concentrated in vacuo and theresidue was purified by RP HPLC using a C18 column with a gradient ofH₂O, 0.1% TFA-acetonitrile, to provide the desired product. ¹H NMR(d-DMSO, 400 MHz) δ 10.46 (s, 1H), 8.48 (d, 1H), 8.25 (d, 1H), 7.66 (d,1H), 7.2-7.3 (m, 1H), 7.1-7.2 (d, 1H), 6.9-7.0 (m, 2H), 6.78 (s, 1H),6.65-6.75 (m, 2H), 6.53 (d, 1H), 5.56 (q, 1H), 3.41 (q, 2H), 2.8-3.0 (m,2H), 1.5-1.6 (m, 1H), 1.8-1.9 (m, 2H), 1.6-1.7 (m, 2H); MS (m/z) 472[M+H]⁺

Example 54

Synthesis of (S)-tert-butyl1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(54A)

A round bottom flask was charged with 50A (3 g, 7.3 mmol), DME (100 ml),3-carbamoyl-4-fluorophenylboronic acid (1.6 g, 8.7 mmol), Pd(PPh₃)₄ (419mg, 0.36 mmol) and K₂CO₃ (2 g, 14.5 mmol) dissolved in water (12 ml).Heat the stirring mixture overnight at 85° C. Allow the reaction to coolthen dilute with H₂O and extract 2× EtOAc. The combined organic layerswere washed with brine then dried over sodium sulfate, concentrated, andpurified by flash chromatography to give the title compound (1.8 g,53%): MS (m/z) 472.6 [M+H]⁺.

Synthesis of(S)-5-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamidetriflouroacetate (54B)

A round bottom flask was charged with (S)-tert-butyl1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(1 g, 2.2 mmol) and TFA:DCM 1:1 (4 ml). The reaction was stirred at roomtemperature until complete disappearance of starting materials thenconcentrated 2× from DCM. The crude solid was used as is in nextreaction: MS (m/z) 372.4 [M+H]⁺.

Synthesis of methyl 2-oxo-2-(5-(trifluoromethyl)-1H-indol-3-yl)acetate(54D)

A round bottom flask was charged with ether (2 ml) and5-(trifluoromethyl)-1H-indole (3 g, 16.2 mmol) followed by slow additionof oxalyl chloride (3 ml, 34 mmol). The reaction was stirred for 15minutes after complete addition of all reagents then filtered. The cakewas rinsed with ether then soaked in 6 ml methanol after which themethanol was filtered off (repeated 3 times). Drying under vacuum gave 3g of the desired compound as the HCl salt which was used with no furtherpurification. The yield was 60%. MS (m/z) 272.1 [M+H]⁺.

Synthesis of methyl 2-(5-(trifluoromethyl)-1H-indol-3-yl)acetate (54E)

A round bottom is charged with methyl2-oxo-2-(5-(trifluoromethyl)-1H-indol-3-yl)acetate (3 g, 9.8 mmol),dioxane (200 ml), Pd/C (1 g), H₂NaO₂P—H₂O (6 g, 57 mmol), and H₂O (18ml). The resulting mixture was stirred at 125° C. until completedisappearance of starting material. The reaction mixture was cooled toRT and filtered over a plug of celite, rinsing with ethyl acetate. Thelayers were partitioned and the organic layer was dried over sodiumsulfate, filtered, concentrated and purified by flash chromatography togive the desired compound (1.3 g, 50%): MS (m/z) 258.1 [M+H]⁺.

Synthesis of 2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid (54F)

A round bottom flask was charged with methyl2-(5-(trifluoromethyl)-1H-indol-3-yl)acetate (1.4 g, 5.3 mmol), methanol(2 ml), and THF (6 ml). To the resulting mixture was added a solution ofLiOH (638 mg, 27 mmol) dissolved in water (2 ml). The mixture wasstirred until done after which the mixture was diluted with ethylacetate and the layers separated, the aqueous layer was acidified andextracted 2× with ethyl acetate and the combined organic layers weredried over sodium sulfate, filtered and concentrated to give the desiredcompound (1.3 g. 99%): MS (m/z) 244.1 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-(trifluoromethyl)-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(54G)

A 2 dram vial was charged with 54F (25 mg, 0.13 mmol), 54B (50 mg, 0.13mmol), HATU (50 mg, 0.13 mmol), DiPEA (0.1 ml, 0.6 mmol) and DMF (1.5ml). The mixture was stirred until done by LC/MS then diluted with a 1:1mixture of TFA:water (0.5 ml), filtered and purified by HPLC to affordthe desired compound (16.8 mg, 28%): ¹H NMR (400 MHz, dmso) δ 11.24 (s,1H), 8.70 (d, 1H), 8.63 (dd, 1H), 7.80 (s, 1H), 7.63 (d, 2H), 7.56 (dd,1H), 7.50-7.42 (m, 2H), 7.37 (dd, 2H), 7.31-7.17 (m, 3H), 6.82 (t, 1H),6.48 (d, 2H), 5.14 (dd, 1H), 3.52 (s, 2H), 2.96 (d, 2H); MS (m/z) 597.6[M+H]⁺.

Example 55

Synthesis of 2-(5-fluoro-1H-indol-3-yl)acetic acid (55B)

To a suspension of 55A (140 g, 861 mmol, 1.0 eq), alpha-ketoglutaricacid (151 g, 1.03 mol) in conc. HCl (1500 mL) and H₃PO₄ (600 mL) wasadded dropwise pyridine (450 mL) while keeping the temperature below 10°C. After addition, the suspension was refluxed for 4 hours. Uponcooling, the mixture was extracted with ether (1000 mL 5). The combinedorganic layer was dried with anhydrous Na₂SO₄, concentrated to afford120 g of crude title compound as a blackish green solid, which was usedfor the next step without any further purification.

Synthesis of Methyl 2-(5-fluoro-1H-indol-3-yl)acetate (55C)

To a suspension of 55B (130 g, crude) in MeOH (1000 mL) was addeddropwise SOCl₂ (120 g, 1.00 mol) while keeping the temperature below 10°C. After addition, the suspension was refluxed for 3 hours. Aftercooling and concentration, the residue was diluted with DCM (1000 mL)and H₂O (500 mL). The organic layer was washed with saturated NaHCO₃solution, dried and concentrated. The residue was purified by silicachromatography (PE/EtOAc from 50/1 to 10/1) to afford 20.5 g of thetitle compound as a pale solid.

Synthesis of 2-(5-fluoro-1H-indol-3-yl)acetic acid (55B) bySaponification

Compound 55B was saponified by a method analogous to Example 74C.

Synthesis of(S)-1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethanaminehydrochloride (55D)

Dissolved 50B (4.4 g, 10.7 mmol) in 20 ml 4N HCl/1,4-dioxane. Thereaction was stirred for 1 hr at room temperature then concentrated invacuo. Azeotroped residue 3× with Et₂O, then dried under vacuum to give3.7 g of the title compound as an off white solid.

Synthesis of(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(55E)

Dissolved 55B (151 mg, 0.780 mmol) and 55E (300 mg, 0.858 mmol) in DMF(8 ml) Diisoproplyethylamine (791 ul, 2.57 mmol) and HATU (326 mg, 0.858mmol) were added and the reaction was stirred at room temperatureovernight. The reaction was partitioned between EtOAc and H₂O. Theaqueous layer was extracted 2×EtOAc. The combined organics were washed2× brine, dried and concentrated. Purified crude product on SiO₂ elutingwith EtOAc/hexanes. Concentration of the purified fractions gave 373 mgof the title compound. MS (m/z) 488.7 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-fluoro-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(55)

To a solution of 55E (50 mg, 0.102 mmol) and 4-fluoro-3carbamoylphenylboronic acid (21 mg, 0.113 mmol) in DME (1 ml) was added 0.4N aq.K₂CO₃ (515 ul) and Pd(PPh₃)₄ (11.9 mg, 0.0010 mmol). The resultingmixture was heated at 110° C. for 10 min. in a microwave. The reactionmixture was filtered, washed 1× with DMF and the solution was purifiedby RP HPLC using a C18 column with a gradient of 0.1%/H₂O, 0.1%TFA-acetonitrile, to provide 37 mg of the title compound. ¹H NMR (400MHz, dmso) δ 10.87 (s, 1H), 8.81-8.53 (m, 2H), 7.66 (d, 2H), 7.56 (d,1H), 7.47 (dd, 1H), 7.39-7.32 (m, 1H), 7.30-7.17 (m, 2H), 7.15-7.04 (m,2H), 6.83 (ddd, 2H), 6.51 (d, 2H), 5.12 (dd, 1H), 3.51-3.31 (m, 2H),2.98 (dd, 2H). MS (m/z) 547 [M+H]⁺.

Example 56

Synthesis of(S)-5-(2-(1-(2-chloroacetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(56A)

A round bottom flask was charged with(S)-5-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(800 mg, 7.7 mmol), DCM (20 ml), and DiPEA (0.8 ml, 4.6 mmol). To thestirring mixture slowly add 2-chloroacetyl chloride (0.16 ml, 2 mmol)and allow to stir 30 minutes then quench with H₂O. Extract 2×DCM Thecombined organic layers were dried over sodium sulfate, concentrated,and purified by flash chromatography to give the desired compound (460mg, 61%): MS (m/z) 448.5 [M+H]J.

Synthesis of(S)-5-(2-(1-(2-(1H-benzo[g]indol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(56B)

A 2 dram vial was charged with 1H-benzo[g]indole (11.7 mg, 0.07 mmol),KHMDS (13.9 mg, 0.07 mmol), and DMF (1.5 ml). The resulting mixture wasstirred for 10 minutes then(S)-5-(2-(1-(2-chloroacetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(30 mg, 0.07 mmol) was added. The mixture was stirred until done byLC/MS then diluted with a 1:1 mixture of TFA:water (0.5 ml), filteredand purified by HPLC to afford the desired compound (5.4 mg, 13%): ¹HNMR (400 MHz, dmso) δ 9.09 (d, 1H), 8.73 (d, 1H), 7.91 (d, 1H), 7.85 (d,1H), 7.57 (dd, 4H), 7.40 (dd, 3H), 7.29 (d, 3H), 7.19 (dd, 2H), 6.93 (s,1H), 6.51 (d, 3H), 5.25 (s, 2H), 5.16 (d, 1H), 3.02 (d, 2H); MS (m/z)579.8 [M+H]⁺.

Example 57

Synthesisof(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(57A)

To a solution of 55D (3.73 g, 10.7 mmol) and diisopropylethylamine (5.07ml, 29.1 mmol) was added2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid(2.41 g, 9.71 mmol) and2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate (HATU, 3.69 g, 9.71 mmol). The reaction mixture wasstirred 16 hrs at room temperature and then concentrated under reducepressure. The residue was dissolved in hot CH₂Cl₂ and filtered to removeinsoluble material. The filtrate was reheated and allowed to cool. Thesolid that formed was collected by filtration, washed with hexanes andair dried. The mother liquors were concentrated and the residue wasrecyrstallized from EtOAc/hexanes. Recovered a total of 4.2 g of thetitle compound. MS (m/z) 544.7 [M+H]⁺.

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(3-(methylsulfonyl)phenyl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(57B)

Dissolved 57A (49.4 mg, 0.091 mmol) and 3-methylsulfonylphenyl boronicacid (20 mg, 0.1 mmol) in 4:1 DMEDMF (1 ml). Added 2N aq. K₂CO₃ (100 ul)and Pd(PPh₃)₄ (12 mg, 0.01 mmol) and then heated the reaction at 100° C.under N₂ for 16 hrs. The reactions were cooled, diluted with H₂O andextracted with EtOAc (2×). The organic layer was concentrated underreduced pressure. The residue was purified by RP HPLC using a C18 columnwith a gradient of 0.1%/H₂O, 0.1% TFA-acetonitrile to give 2.6 mg of thetitle compound. MS (m/z) 619 [M+H]⁺.

Example 58

Synthesis of 5-ethyl-3-(trifluoromethyl)-1H-pyrazole (58B)

To a solution of 1,1,1-trifluorohexane-2,4-dione (8.4 g, 50 mmol) inEtOH (100 mL) was slowly added hydrazine hydrate (5.0 g, 50 mmol). Thereaction was stirred at room temperature for 1 h and then heated toreflux for 1 h. The reaction was cooled to room temperature and thesolvent was removed in vacuo to give 8 g of the title compound. MS(m/z): 165.0 [M+H]⁺; HPLC retention time 0.77 min (2-98%acetonitrile:water with 0.05% trifluoroacetic acid).

Synthesis of 4-bromo-5-ethyl-3-(trifluoromethyl)-1H-pyrazole (58C)

To a solution of 5-ethyl-3-(trifluoromethyl)-1H-pyrazole (3.3 g, 20mmol) in CHCl₃ (100 mL) was added NBS (4.3 g, 24 mmol). The reaction wasstirred at room temperature overnight and was then poured into ethylacetate and washed with saturated Na₂S₂O₃ solution and brine. Theorganic layer was dried over sodium sulfate, filtered and concentrated.The resulting residue was purified by silica gel chromatography elutingwith EtOAc/hexanes to afford 4.8 g of the title product. MS (m/z): 243.1[M+H]⁺; HPLC retention time 0.98 min (2-98% acetonitrile:water with0.05% trifluoroacetic acid).

Synthesis of(S)-5-(2-(1-(2-(4-bromo-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(58D)

To a solution of 4-bromo-5-ethyl-3-(trifluoromethyl)-1H-pyrazole (290mg, 1.2 mmol) in DMF (5 mL) was added potassium tert-butoxide (168 mg,1.5 mmol) at room temperature. After stirred at rt for 10 min,(S)-5-(2-(1-(2-chloroacetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(447 mg, 1 mmol) was added in one portion. The reaction was stirred atroom temperature for 1 h and was then poured into ethyl acetate andwashed with saturated NH₄Cl solution and brine. The organic layer wasdried over sodium sulfate, filtered and concentrated. The resultingresidue was purified by silica gel chromatography eluting withEtOAc/hexanes to afford 430 mg of the title product. MS (m/z): 656.1[M+H]⁺; HPLC retention time 1.22 min (2-98% acetonitrile:water with0.05% trifluoroacetic acid). ¹H NMR (400 MHz, cdcl₃) δ 8.56 (s, 1H),7.61 (d, J=5.1 Hz, 1H), 7.50 (s, 1H), 7.31 (s, 1H), 7.29-7.13 (m, 3H),6.75 (s, 1H), 6.55 (s, 1H), 6.12 (d, J=6.4 Hz, 2H), 5.79 (s, 1H), 5.43(d, J=7.4 Hz, 1H), 4.79 (d, J=3.5 Hz, 2H), 2.87 (m, 2H), 2.65 (q, J=7.6Hz, 2H), 1.09 (t, J=7.6 Hz, 3H).

Example 59

Synthesis of(S)—N—((S)-1-(3-bromopyridin-2-yl)-2-(3-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(59A)

Compound 59A was prepared according to the method presented for thesynthesis of Example 38 substituting (3-fluorobenzyl)magnesium chloridefor (3,5-difluorobenzyl)magnesium bromide and 38B to provide of 1.2 g oftitle compound. MS (m/z) 399 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-bromopyridin-2-yl)-2-(3-fluorophenyl)ethyl) carbamate (59B)

Compound 59B was prepared according to the method presented for thesynthesis of Example 50 substituting 59A for 38C to provide 0.5 g oftitle compound: MS (m/z) 395 [M+H]⁺.

Synthesis of (S)-tert-butyl(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3-fluorophenyl)ethyl)carbamate(59C)

Compound 59C was prepared according to the method presented for thesynthesis of Example 50 utilizing 59B for 50A and(3-carbamoyl-4-fluorophenyl)boronic acid to provide 450 mg of titlecompound: MS (m/z) 454 [M+H]⁺.

Synthesis of(S)-5-(2-(1-amino-2-(3-fluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamidehydrochloride (59D)

4N HCl/1,4-dioxane (5.0 ml) was added to 59C (0.45 g, 10 mmol). LC/Massshowed completion of reaction after 10 min. Concentrated reactionmixture in vacuo to give 360 mg of title compound: MS (m/z) 354 [M+H]⁺.

Synthesis of5-(2-((1S)-1-(2-(4,6-dimethyl-2-oxoindolin-3-yl)acetamido)-2-(3-fluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(59E)

Combined 59D (36 mg, 0.1 mmol), 2-(4,6-dimethyl-2-oxoindolin-3-yl)aceticacid (22 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) in 1 ml vial. AddedDMF and stirred to dissolve the solids. Added diisopropylethylamine (45ul, 0.26 mmol) and stirred reaction at room temperature for 90 min.LC/MS shows desired product with a small amount of acid. Purifiedreaction mixture on prep reverse phase HPLC using 20-80% B over 20 min.(A=0.1% TFA/H₂O; B=0.1% TFA/Acetonitrile). Combined pure fractions asdetermined by LC/MS and lyophilized to provide 35 mg of title compound.¹H NMR (400 MHz, cd₃od) δ 8.63 (ddd, 2H), 7.67 (dd, 1H), 7.58 (dd, 1H),7.51-7.09 (m, 8H), 7.14 (s, 1H), 7.16-6.95 (m, 3H), 6.81 (dd, 2H), 6.69(d, 2H), 6.57 (d, 2H), 6.53-6.32 (m, 4H), 5.27 (dd, 2H), 3.95 (d, 2H),3.05-2.76 (m, 6H), 2.76-2.59 (m, 3H), 2.34 (s, 1H), 2.24 (d, 51H), 2.14(d, 5H); MS (m/z) 555 [M+H]⁺.

Example 60

Synthesis of ethyl2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(60A) and ethyl2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-2-yl)acetate(60B)

Compound 60A and 60B were prepared according to the method presented forthe synthesis of Example 122 substituting ethyl 2,2-difluoroacetate forethyl 2,2,2-trifluoroacetate to provide 1.7 g of 60A and 0.33 g of 60B.60A: MS (m/z) 257 [M+H]⁺ and 60B: MS (m/z) 257 [M+H]⁺.

Synthesis of 2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (60G)

Compound 60G was prepared according to the method presented for thesynthesis of Example 181 substituting 60A for 122D to provide 140 mg oftitle compound. MS (m/z) 265 [M+H]⁺.

Synthesis of 5-(2-((1S)-1-(2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(60H)

Compound 60H was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and 60G to provide 254 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.66 (dd, 1H), 7.54 (ddd, 1.7 Hz,1H), 7.27 (dddd, 4H), 6.82 (d, 1H), 6.73-6.57 (m, 2H), 6.54 (d, 1H),6.37-6.19 (m, 2H), 5.42-5.27 (m, 1H), 4.39-4.22 (m, 1H), 4.07 (q, 1H),3.23-2.91 (m, 2H), 2.51-2.38 (m, 2H), 1.98 (s, 1H), 1.82 (s, 1H),1.97-1.17 (m, 4H), 1.15-0.97 (m, 1H), 0.89 (t, 1H). MS (m/z) 618 [M+H]⁺.

Example 61

Synthesis of (S)-tert-butyl1-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(61D)

A round bottom flask was charged with 50A (1 g, 2.4 mmol), DME (8 ml),DMF (2 ml),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(886 mg, 3.6 mmol), LiCl (308 mg, 7.2 mmol), Pd(PPh₃)₂Cl₂ (85 mg, 0.12mmol) and Na₂CO3 (513 mg, 4.8 mmol) dissolved in water (2 ml). Microwavethe reaction at 150° C. for 20 minutes. Allow the reaction to cool thendilute with H₂O and extract 2× EtOAc. The combined organic layers werewashed with brine then dried over sodium sulfate, concentrated, andpurified by flash chromatography to give the desired compound (785 mg,72%): MS (m/z) 451.3 [M+H]⁺.

Synthesis of(S)-1-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethanaminehydrochloride (61E)

A round bottom flask was charged with (S)-tert-butyl1-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(549 mg, 1.2 mmol) and 4 N HCl/dioxane (3 ml). The reaction was stirredat room temperature until done by LC/MS then concentrated 2× from DCM.The crude solid was used as is in next reaction: MS (m/z) 351.2 [M+H]⁺.

Synthesis of(S)—N-(1-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide(61F)

The title compound was prepared according to the method presented in thesynthesis of 34E substituting 61C for 34D and 61E for(S)-2-(3,5-difluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethanamineto provide the desired compound (16.8 mg, 33%): ¹H NMR (400 MHz, cd₃od)δ 8.72 (d, 1H), 8.01 (s, 1H), 7.85 (s, 1H), 7.66 (d, 1H), 7.56 (d, 1H),7.44 (dd, 4.8 Hz, 1H), 6.70 (s, 1H), 6.62 (d, 1H), 6.28 (d, 2H), 6.23(s, 1H), 5.42-5.20 (m, 1H), 4.99 (s, 2H), 4.82-4.88 (m, 1H), 3.46 (s,1H), 3.12-2.99 (m, 2H), 1.63 (s, 1H), 0.94-0.84 (m, 2H), 0.63 (s, 2H);MS (m/z) 567.5 [M+H]⁺.

Example 62

Synthesis of(S)—N-cyclopropyl-3-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(62)

Prepared 29 mg of the title compound by a method analogous to compound57B using 57A and 3-(cyclopropylcarbamoyl)phenylboronic acid. MS (m/z)624 [M+H]⁺.

Example 63

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(5-fluoro-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)-5-fluoro-N-methylbenzamide(63)

Prepared 16 mg of the title compound by a method analogous to 55F using3-fluoro-5-(methylcarbamoyl)phenylboronic acid and 55E. MS (m/z) 561[M+H]J.

Example 64

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(6′-methoxy-3,3′-bipyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(64)

Prepared 22 mg of the title compound by a method analogous to 55F using6-methoxypyridin-3-ylboronic acid and 55E. MS (m/z) 544 [M+H]⁺.

Example 65

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-fluoro-3-methylphenyl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(65)

Prepared 33.5 mg of the title compound by a method analogous to compound57B using 57A and 3-methyl-4-fluorophenyl boronic acid. MS (m/z) 573[M+H]⁺.

Example 66

Synthesis of(S)—N-cyclopropyl-3-(2-(2-(3,5-difluorophenyl)-1-(2-(5-fluoro-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(66)

Prepared 1.5 mg of the title compound by a method analogous to 55F using[3-(cyclopropylaminocarbonyl)phenyl] boronic acid and 55E. MS (m/z) 569[M+H]⁺.

Example 67

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(67)

Prepared 34.9 mg of the title compound by a method analogous to 55Fusing 3-trifluoromethoxy-phenylboronic acid and 55E. MS (m/z) 570[M+H]⁺.

Example 68

Synthesis of(S)—N-(1-(3-bromo-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(68A)

Prepared 1.5 g of the title compound by a method analogous to 55E using60G and 55B. MS (m/z) 560 [M+H]⁺.

Synthesis of (S)-methyl4-(2-(1-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-ylacetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)phenylcarbamate(68B)

To a solution of 68A (28 mg, 0.05 mmol) and(4-(methoxycarbonylamino)phenylboronic acid (19.5 mg, 0.1 mmol) in 4:1DME/DMF (500 ul) was added LiCl (6.4 mg, 0.15 mmol), 1N aq. Na₂CO₃ (125ul, 0.125 mmol), and Pd(PPh₃)₂Cl₂ (7 mg, 0.01 mmol). The reaction washeated in a microwave synthesizer at 150° C. for 15 min. The cooledsuspension was filtered and the filtrate was purified by RP HPLC using aC18 column with a gradient of 0.1%/H₂O, 0.1% TFA-acetonitrile to give18.5 mg of the title compound. MS (m/z) 630 [M+H]⁺.

Example 69

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-p-tolylpyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(69)

Prepared 36.3 mg of the title compound by a method analogous to 55Fusing 4-methyl-phenylboronic acid and 55E. MS (m/z) 500 [M+H]⁺.

Example 70

Synthesis of(S)—N-(1-(3-(4-(N-isopropylsulfamoyl)phenyl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide (70)

Prepared 8.4 mg of the title compound by a method analogous to 68B using68A and N-isopropyl 4-boronobenzenesulfonamide. MS (m/z) 678 [M+H]⁺.

Example 71

Synthesis of(S)—N-(1-(3-(4-((piperidin-1-yl)sulfonyl)phenyl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(71)

Prepared 14.8 mg of the title compound by a method analogous to 68Busing 68A and 4-(piperidin-1-ylsulfonyl)phenylboronic acid. MS (m/z) 704[M+H]⁺.

Example 72

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(thiophen-3-yl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(72)

Prepared 29 mg of the title compound by analogous method to 55F usingthiophen-3-yl-boronic acid and 55E. MS (m/z) 492 [M+H]⁺.

Example 73

Synthesis of(S)—N-(1-(3-(1-methylindazole-6-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(73)

Prepared 21.1 mg of the title compound by a method analogous to 68Busing 68A and 1-methylindazole-6-boronic acid. MS (m/z) 611 [M+H]⁺.

Example 74

Synthesis of ethyl2-(L-4,5,6,7-Tetrahydro-3-trifluoromethyl-7,8,8-trimethyl-1H-4,7-(methano)indazol-1-yl)acetate(74B)

To a suspension ofL-4,5,6,7-tetrahydro-3-trifluoromethyl-7,8,8-trimethyl-1H-4,7-(methano)indazole(977 mg, 4 mmol), Cs₂CO₃ (1.6 g, 8.3 mmol) in DMF (6 ml) was added ethylbromoacetate as a solution in 5 ml of DMF. The reaction was stirred atroom temperature for 5 hrs, then diluted with water. The mixture wasextracted with EtOAc. The organics were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by SiO₂ chromatographyeluting with a gradient of EtOAc in hexanes. Concentrated pure fractionsto give 300 mg of the title compound.

Synthesis ofL-4,5,6,7-Tetrahydro-3-trifluoromethyl-7,8,8-trimethyl-1H-4,7-(methano)indazol-1-yl)aceticacid (74C)

Dissolved 74B (300 mg, 0.908 mmol) in THF (5 ml) and MeOH (2.5 ml).Added 2.5 ml of 2.5N aq. LiOH and stirred the reaction for 30 min. atroom temperature. The mixture was then acidified to pH=3 with 1N aq. HCland extracted 3× with EtOAc. The combined organics were washed withbrine, dried over MgSO₄, filtered and concentrated. Obtained 265 mg ofthe title compound after drying overnight under vacuum.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(L-4,5,6,7-Tetrahydro-3-trifluoromethyl-7,8,8-trimethyl-1H-4,7-(methano)indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(74D)

Prepared 60 mg of the title compound by a method analogous to 54G using74C and 54B. ¹H NMR (400 MHz, CD₃OD) δ 8.71 (dd, 1H), 7.67 (dd, 1H),7.49-7.40 (m, 2H), 7.30 (s, 1H), 7.27-7.20 (m, 1H), 6.69 (t, 1H), 6.36(d, 2H), 5.37 (t, 1H), 3.08 (d, 2H), 2.86 (d, 1H), 2.10 (d, 1H), 1.78(t, 1H), 1.30 (t, 1H), 1.20 (s, 3H), 1.07 (s, 1H), 0.92 (s, 3H), 0.71(s, 3H). MS (m/z) 656 [M+H]⁺.

Example 75

Synthesis of(S)—N-(1-(3-(2-methylquinoline-6-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(75)

Prepared 16.1 mg of the title compound by a method analogous to 68Busing 68A and 2-methylquinoline-6-boronic acid pinacol ester. MS (m/z)622 [M+H]⁺.

Example 76

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-m-tolylpyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(76)

Prepared 11.4 mg of the title compound by a method analogous to compound57B using 57A and 3-methylphenyl boronic acid. MS (m/z) 555 [M+H]⁺.

Example 77

Synthesis of(S)—N-(1-(3-(1H-pyrrolo[3,2-b]pyridine-6-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(77)

Prepared 17.4 mg of the title compound by a method analogous to 68Busing 68A and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine.MS (m/z) 597 [M+H]⁺.

Example 78

Synthesis of(S)—N-(1-(3-(2,4-dichlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(78)

Prepared 19.8 mg of the title compound by a method analogous to 55Fusing (2,4-dichlorophenyl)-boronic acid and 55E. MS (m/z) 555 [M+H]⁺.

Example 79

Synthesis of 2-(2,2,2-trifluoroacetyl)cyclohexane-1,3-dione (79B)

To a solution of 1,3-cyclohexanedione (561 mg, 5.0 mmol) and imidazole(340 mg, 5.0 mmol) in CH₂Cl₂ (50 mil) was added neat N-trifluoroacetylimidazole (2.27 ml, 20 mmol). The reaction mixture was stirred at roomtemperature for 45 min. The reaction was diluted with 4N aq. HCl and thelayers were separated. The aqueous layer was extracted 2× CH₂Cl₂. Thecombined organics were washed with H₂O and brine. The organics weredried over MgSO₄, filtered and concentrated. The crude product was useddirectly for the next step.

Synthesis of 3-(trifluoromethyl)-6,7-dihydro-1H-indazol-4(5H)-one (79C)

To a solution of crude 79B in EtOH (5 ml) was added hydrazine hydrate(500 ul, 7.8 mmol). The reaction was heated at 70° C. for 2.5 hrs andthen concentrated under reduced pressure. The crude product was useddirectly for the next step.

Synthesis of tert-butyl2-(4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(79D)

To a solution of crude 79C in DMF (25 ml) was added potassiumhexamethyldisilazane (997 mg, 5 mmol). The reaction mixture was stirredfor 2 min. at room temperature and then neat alpha-bromo-t-butylacetatewas added. The reaction was stirred 1 hr at room temperature and thenconcentrated under reduced pressure. The residue was portioned betweenEtOAc and H₂O. The aqueous was extracted 2× EtOAc. The combined organicswere washed with brine, dried over MgSO4, filtered and concentrated.Purified crude product on SiO₂ eluting with a gradient of EtOAc inhexanes to give 458 mg of the title compound. MS (m/z) 319 [M+H]⁺.

Synthesis of2-(4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid (79E)

Prepared 508 mg of the title compound using a method analogous to 83Eusing 79D. MS (m/z) 263 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(79F)

Prepared 9.1 mg of the title compound by a method analogous to 54F using54B and 79E. MS (m/z) 616 [M+H]⁺.

Example 80

Synthesis of(S)—N-(1-(3-(4-(pyrrolidinylcarbonylamino)phenyl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(80)

Prepared 9.3 mg of the title compound by a method analogous to 68B using68A and 4-(pyrrolidinylcarbonylamino)phenylboronic acid, pinacol ester.MS (m/z) 655 [M+H]⁺.

Example 81

Synthesis of (4-oxocyclohexyl)methyl 4-methylbenzenesulfonate (81B)

To a 0° C. solution of Compound 81A (10 g, 78 mmol) in pyridine (78 ml)was added 4-toluenesulfonyl chloride (16.7 g, 87.8 mmol) in portions of5 min. The reaction was stirred at 16 hrs at room temperature. Thereaction was poured into 400 ml of a 1:1 mixture of Et₂O/H₂O. The layerswere separated and the organic layer was extracted 2× with Et₂O. Thecombined organics were washed with H₂O (5×) and brine (2×). The organicswere dried over MgSO₄, filtered and concentrated. Purified the crudeproduct on SiO₂ eluting with a gradient of EtOAc in hexanes to give 18.5g of the title compound after drying under reduced pressure. MS (m/z)283 [M+H]⁺.

Synthesis of bicyclo[3.1.1]heptan-2-one (81C)

Potassium hydride (30% oil dispersion, 9.49 g, 71 mmol) was washed 3×with pentane and the dried under a stream of N₂. The solid was thensuspended in THF (259 ml). Compound 81B (10 g, 35.5 mmol) was dissolvedin THF (43 ml) and the resulting solution was added to the potassiumhydride suspension over 5 min. The resulting mixture was heated at 50°C. for 16 hrs. The cooled reaction mixture was filtered through asintered glass funnel to remove gelatinous precipitate. The filtrate wasconcentrated to a small volume (150 ml) and poured into an icewater/ether mixture. The layers were separated and the aqueous layer wasextracted 3× with Et₂O. The combined organics were washed with H₂O (3×),brine (1×), dried over MgSO₄, filtered and concentrated to a smallvolume. The crude material was used without further purification(assumed 40% yield).

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4,5,6,7-tetrahydro-3-carboethoxy-5,7-(methano)indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(81D)

Prepared 2.01 g of the title compound by method analogous to Compound 90starting with compound 81C. MS (m/z) 618 [M+H]⁺.

Example 82

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-(morpholinosulfonyl)phenyl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(82)

Prepared 25.2 mg of the title compound by a method analogous to 55Fusing 4-(morpholinosulfonyl)phenyl boronic acid and 55E. MS (m/z) 635[M+H]⁺.

Example 83

Synthesisof(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4,5,6,7-tetrahydro-3-difluoromethyl-4,7-(methano)indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(83)

The crude Compound 403 (100 mg, 0.174 mmol) was dissolved in CH₂Cl₂ (2ml). The resulting solution was treated with diethylaminosulfurtrifluoride (DAST) (49 ul, 0.376 mmol) at room temperature for 5 hrs.The reaction mixture was poured into sat. aqueous NaHCO₃. The layerswere separated and the organic layer was washed 2× H₂O and 1× brine. Theorganics were dried over MgSO₄, filtered and concentrated. The residuewas purified by RP HPLC using a C18 column with a gradient of 0.1%/H₂O,0.1% TFA-acetonitrile to give 13.7 mg of the title compound. MS (m/z)596 [M+H]⁺.

Example 84

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(84)

Prepared 28.1 mg of the title compound by a method analogous to compound57B using 57A and 3-trifluoromethoxyphenyl boronic acid. MS (m/z) 625[M+H]⁺.

Example 85

Synthesis of(S)—N-(1-(3-(pyrido[2,3-b]pyrazin-7-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(85)

Prepared 2.5 mg of the title compound by a method analogous to 68B using68A and pyrido[2,3-b]pyrazin-7-ylboronic acid, pinacol ester. MS (m/z)610 [M+H]⁺.

Example 86 Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(6-fluoro-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(86)

Prepared 49 mg of the title compound by a method analogous to 50D using6-fluoro-3-indole acetic acid. ¹H NMR (400 MHz, d6-DMSO) δ 10.82 (s,1H), 8.66 (dd, 2H), 7.92 (d, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.61 (dd,1H), 7.49-7.35 (m, 4H), 7.26 (dd, 1H), 7.05-6.98 (m, 2H), 6.91 (t, 1H),6.74-6.61 (m, 1H), 6.49 (d, 2H), 5.17 (dd, 3H), 4.70-4.65 (m, 1H), 3.44(q, 2H), 2.95 (d, 2H). MS (m/z) 529 [M+H]⁺.

Example 87

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4,5,6,7-tetrahydro-3-difluoromethyl-5,7-(methano)indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(87)

Prepared 41.6 mg of the title compound by method analogous to compound83 starting with compound 96. MS (m/z) 596 [M+H]⁺.

Example 88

Synthesis of 2-cyclopropyl-4-(trifluoromethyl)-1H-imidazole (88B)

To a suspension of 3,3-dibromo-1-trifluoromethyl-propane (2.0 g, 7.41mmol) in H₂O (10 ml) was added sodium acetate (1.33 g, 16.2 mmol). Themixture was heated at 100° C. for 30 min and then cooled to roomtemperature. A solution of cyclopropylcarboxaldehyde (646 ul, 8.64 mmol)in of MeOH (4 ml) was added to the reaction mixture followed by NH₄OH(2.8 ml, 20% in H₂O). The reaction was stirred at room temperatureovernight. The mixture was extracted 3× with EtOAc. The combinedorganics were washed with brine, dried over MgSO₄, filtered andconcentrated to give 1.07 g of crude title product which was useddirectly for the next step.

Synthesis ofmethyl-2-(2-cyclopentyl-4-(trifluoromethyl)-1H-imidazol-1-yl)acetate(88C)

The crude product 88B was dissolved in DMF (60 ml). Solid KHMDS (1.45 g,7.29 mmol) was added and the reaction was stirred 5 min. at roomtemperature. Added methyl bromoacetate (690 ul, 7.29 mmol) and thenstirred the reaction for 1 hr at room temperature. The mixture wasconcentrated under reduced pressure to a small volume then partitionedbetween EtOAc and H₂O. Extracted the aqueous layer 2× EtOAc. Thecombined organics were washed with brine, dried over MgSO₄, filtered andconcentrated. The crude product was purified by column chromatography onSiO₂ to give 630 mg of the title compound.

Synthesis of 2-(2-cyclopentyl-4-(trifluoromethyl)-1H-imidazol-1-yl)acetic acid (88D)

Prepared 83 mg of the title compound by a method analogous to 74C using88C.

Synthesis of(S)-5-(2-(1-(2-(2-cyclopropyl-4-(trifluoromethyl)-1H-imidazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(88E)

Prepared 29.4 mg of the title compound by a method analogous to 54Gusing 88D and 54B. MS (m/z) 588 [M+H]⁺.

Example 89

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(6′-fluoro-5′-methyl-3,3′-bipyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(89)

Prepared 28.2 mg of the title compound by a method analogous to compound57B using 57A and 6-fluoro-5-methylpyridin-3-ylboronic acid. MS (m/z)574 [M+H]⁺.

Example 90

Synthesis of ethyl 3-oxobicyclo[2.2.1]heptane-2-carboxylate (90B)

Suspended NaH (400 mg, 10 mmol) in toluene (8 ml). Added diethyloxalyate (1.26 ml, 9.2 mmol) and heated mixture to 60° C. Added asolution of norboranone (850 mg, 7.7 mmol) in toluene (4 ml). Stirredreaction mixture for 1 hr. Cooled reaction to room temperature and thepoured into ice. Neutralized aqueous layer to pH=2 with 1N aq. HCl.Extracted mixture 3× with EtOAc. The combined organics were washed withbrine, dried over MgSO₄, filtered and concentrated. Purified residue onSiO₂ column using a gradient of EtOAc and hexanes to give 1.33 g of thetitle compound.

Synthesis of 4,5,6,7-tetrahydro-3-carboethoxy-4,7-(methano)indazole(90C)

Dissolved 90B (1.33 g, 6.33 mmol) in EtOH (13 ml). Added hydrazinehydrate (405 ul, 6.33 mmol) and heated reaction to 70° C. Stirredreaction for 72 hrs at 70° C. Cooled reaction to room temperature, thenpartition mixture between EtOAc and H₂O. Extracted aqueous layer 1×EtOAc. Dried combined organic over MgSO₄, filtered and concentrated.Purified the residue on SiO₂ column using a gradient of EtOAc andhexanes to give 497 mg of the title compound. MS (m/z) 206 [M+H]⁺.

Synthesis of t-butyl2-(4,5,6,7-tetrahydro-3-carboethoxy-4,7-(methano)indazol-1-yl)acetate(90D)

Prepared 542 mg of the title compound by a method analogous to 107Cusing 90C. MS (m/z) 321 [M+H]⁺.

Synthesis of2-(4,5,6,7-tetrahydro-3-carboethoxy-4,7-(methano)indazol-1-yl)aceticacid (90E)

Prepared 455 mg of the title compound by a method analogous to 107Dusing 90D. MS (m/z) 265 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4,5,6,7-tetrahydro-3-carboethoxy-4,7-(methano)indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(90F)

Prepared 236 mg of the title compound using a method analogous to 107Eusing 90E and 54B ¹H NMR (400 MHz, CD₃OD) δ 8.69 (s, 1H), 7.65 (t, 1H),7.44 (s, 2H), 7.31 (s, 1H), 7.26-7.17 (m, 1H), 6.66 (d, 1H), 6.35 (d,2H), 5.35 (d, 1H), 4.30 (q, 2H), 3.50 (s, 1H), 3.05 (d, 2H), 1.87 (d,4H), 1.66 (s, 1H), 1.34 (t, 3H), 1.09 (s, 2H). MS (m/z) 618 [M+H]⁺.

Example 91

Synthesis of2-(2-(benzyloxymethyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)acetic acid(91A)

Prepared 115 mg of the title compound by a method analogous to 107Dusing benzyloxyacetaldehyde.

Synthesis of(S)-5-(2-(1-(2-(2-(benzyloxymethyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(91B)

Prepared 81.2 mg of the title compound by a method analogous to 107Eusing 107D and 54B ¹H NMR (400 MHz, CD₃OD) δ 8.69 (s, 1H), 7.57 (d, 2H),7.39 (s, 2H), 7.22 (d, 6H), 6.64 (s, 1H), 6.24 (s, 2H), 5.28 (s, 1H),4.54 (d, 2H), 4.40 (s, 2H), 2.95 (d, 2H). MS (m/z) 668 [M+H]⁺.

Example 92

Synthesis of(S)—N-(1-(3-(3-(benzyloxy)phenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(92)

Prepared 25 mg of the title compound by a method analogous to 55F using3-phenoxy-phenylboronic acid and 55E. MS (m/z) 592 [M+H]⁺.

Example 93

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(D-4,5,6,7-Tetrahydro-3-trifluoromethyl-7,8,8-trimethyl-1H-4,7-(methano)indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(93B)

Prepared 60.9 mg of the title compound by a method analogous to 74Dusing 93A, obtained by a method analogous to 74C, and 54B. ¹H NMR (400MHz, CD₃OD) δ 8.69 (dd, 1H), 7.66 (dd, 1H), 7.46 (dd, 2H), 7.28 (s, 1H),7.24-7.18 (m, 1H), 6.68 (t, 1H), 6.36 (d, 2H), 5.37 (t, 1H), 3.06 (d,2H), 2.84 (d, 1H), 2.06 (d, 1H), 1.76 (t, 1H), 1.24 (d, 1H), 1.16 (s,3H), 1.07-0.94 (m, 1H), 0.90 (s, 3H), 0.73 (s, 3H). MS (m/z) 656 [M+H]⁺.

Example 94

Synthesis of N-((1S)-2-(3,5-difluorophenyl)-1-(3-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(94)

Prepared 2 mg of the title compound by a method analogous to 55F using3,5-dimethyl-1,2-oxazolyl-4-boronic acid and 55E. MS (m/z) 505 [M+H]⁺.

Example 95

Synthesis of (S)-tert-butyl1-(3-(3-cyanophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamate(95A)

Prepared 60 mg of the title compound by a method analogous to 54A using3-cyanophenyl boronic acid.

Synthesis of(S)-3-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzonitriletrifluoroacetate (95B)

Prepared 61.9 mg of the title compound by a method analogous to 54B.

Synthesis of(S)—N-(1-(3-(3-cyanophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(1H-indol-1-yl)acetamide(95C)

Prepared 33 mg of the title compound by a method analogous to 74D usingcompound 95B and indole-1-acetic acid. MS (m/z) 493 [M+H]⁺.

Example 96

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4,5,6,7-tetrahydro-3-formyl-5,7-(methano)indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(96)

Prepared 256 mg of the title compound by a method analogous to compound403 starting with compound 81D. MS (m/z) 574 [M+H]⁺.

Example 97 Synthesis of(S)—N-(1-(3-(quinoline-7-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(97)

Prepared 6.1 mg of the title compound by a method analogous to 68B using68A and quinolin-7-yl-7-boronic acid. MS (m/z) 608 [M+H]⁺.

Example 98

Synthesis of(S)—N-(1-(3-(4-(N-cyclohexylsulfamoyl)phenyl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide (98)

Prepared 17.3 mg of the title compound by a method analogous to 68Busing 68A and 4-(N-cyclohexylsulfamoyl)phenylboronic acid. MS (m/z) 718[M+H]J.

Example 99

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(99)

Prepared 9.5 mg of the title compound by a method analogous to 55F using3-(5-methyl-1,3,4-oxadiazol-2-yl)phenylboronic acid and 55E. MS (m/z)569 [M+H]⁺.

Example 100 Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-isopropoxyphenyl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(100)

Prepared 4.7 mg of the title compound by a method analogous to compound57B using 57A and 4-isoproxyphenyl boronic acid. MS (m/z) 599 [M+H]⁺.

Example 101

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(6′-(pyrrolidin-1-yl)-3,3′-bipyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(101)

Prepared 35.5 mg of the title compound by a method analogous to 55Fusing 6-(pyrrolidin-1-yl)pyridin-3-ylboronic acid and 55E. MS (m/z) 566[M+H]⁺.

Example 102

Synthesis of ethyl2-(3′-(trifluoromethyl)-6′,7′-dihydrospiro[[1,3]dithiolane-2,4′-indazole]-1′(5′H)-yl)acetate(102A)

To a solution of 272A (290 mg, 1.0 mmol) in CH₂Cl₂ was add1,2-ethanedithiol (126 ul, 1.5 mmol) and BF₃.2HOAc (210 ul, 1.5 mmol).The reaction mixture was stirred at room temperature for 16 hrs thenpartitioned between CH₂Cl₂ and water. Extracted the aqueous layer1×CH₂Cl₂. Washed the combined organics 1× with sat. aq. NaHCO₃, H₂O andbrine. Dried the organics over MgSO₄, filtered and concentrated.Purified the crude product on SiO₂ eluting with a gradient of EtOAc inhexanes to give 334 mg of the title compound.

Synthesis of ethyl2-(4,4-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(102B)

A solution of N-iodosuccinimide (423 mg, 1.88 mmol) and HF/pyridine (2.6ml) in CH₂Cl₂ (2.6 ml) in a Teflon reaction vessel was cooled to −70° C.under N₂. A solution of Compound 102A (334 mg, 0.91 mmol) in CH₂Cl₂ (2.6ml) was added to the cooled reaction mixture over 5 min. The resultingmixture was stirred at −70° C. for 45 min. then warmed to −50° C. for 20min. The reaction vessel was placed in an ice bath and the reaction wasquenched with sat. aq. NaHCO₃. The mixture was diluted with CH₂Cl₂ andthe layers were separated. Extracted the aqueous layer 2× CH₂Cl₂. Washedthe combined organics 1× with brine. Dried the organics over MgSO₄,filtered and concentrated. Purified the crude product on SiO₂ elutingwith a gradient of EtOAc in hexanes to give 112 mg of the titlecompound.

Synthesis of Ethyl2-(4,4-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(102C)

Prepared 79.2 mg of the title compound by a method analogous to compound401B using compound 102B.

Synthesis of(S)-5-(2-(1-(2-(4,4-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(102D)

Prepared 130 mg of the title compound by a method analogous to 54F using102C and 54B. ¹H NMR (400 MHz, CD₃OD) δ 8.70 (dd, 1H), 7.65 (d, 1-1),7.45 (dd, 2H), 7.33 (s, 1H), 7.22 (dd, 1H), 6.67 (t, 1H), 6.34 (d, 2H),5.36 (t, 1H₁), 4.86 (d, 2H), 3.07 (d, 2H), 2.57 (d, 2H), 2.17 (d, 2H),2.00 (d, 2H). MS (m/z) 638 [M+H]⁺.

Example 103

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-isobutylphenyl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(103)

Prepared 37 mg of the title compound by a method analogous to 55F using4-isobutylphenylboronic acid and 55E. MS (m/z) 542 [M+H]⁺.

Example 104

Synthesis of(S)—N-(1-(3-(isoquinolin-7-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(104)

Prepared 11.7 mg of the title compound by a method analogous to 68Busing 68A and isoquinolin-7-ylboronic acid. MS (m/z) 608 [M+H]⁺.

Example 105

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-(morpholinosulfonyl)phenyl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(105)

Prepared 38.6 mg of the title compound by a method analogous to compound57B using 57A and 4-(morpholinosulfonyl)phenylboronic acid. MS (m/z) 690[M+H]⁺.

Example 106

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-isopropoxyphenyl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(106)

Prepared 25.4 mg of the title compound by a method analogous to 55Fusing 4-isopropoxyphenylboronic acid and 55E. MS (m/z) 544 [M+H]⁺.

Example 107

Synthesis of 2-cyclopentyl-4-(trifluoromethyl)-1H-imidazole (107B)

To a suspension of 3,3-dibromo-1-trifluoromethyl-propane (2.35 g, 8.72mmol) in H₂O was added sodium acetate (1.67 g, 20.4 mmol). The mixturewas heated at 100° C. for 30 min. and then cooled to room temperature. Asolution of cyclopentanecarboxaldehyde (1 g, 10.2 mmol) in 4.8 ml ofMeOH was added to the reaction mixture followed by NH₄OH (4.8 ml, 20% inH₂O). The reaction was stirred at room temperature overnight. Themixture was extracted 3× with EtOAc. The combined organics were washedwith brine, dried over MgSO₄, filtered and concentrated. The crudeproduct was used directly for the next step.

Synthesis of tert-butyl2-(2-cyclopentyl-4-(trifluoromethyl)-1H-imidazol-1-yl)acetate (107C)

The crude product from 107B (8.72 mmol) was dissolved in 86 ml DMF.Solid KHMDS (2.09 g, 10.5 mmol) was added and the reaction was stirred 5min. at room temperature. Added t-butyl bromoacetate (1.52 ml, 10.5mmol) and then stirred the reaction for 30 min. at room temperature. Themixture was concentrated under reduced pressure to a small volume thenpartitioned between EtOAc and H₂O. Extracted the aqueous layer 2× EtOAc.The combined organics were washed with brine, dried over MgSO₄, filteredand concentrated. The crude product was purified by columnchromatography on SiO₂ to give 279 mg of the title compound.

Synthesis of2-(2-cyclopentyl-4-(trifluoromethyl)-1H-imidazol-1-yl)acetic acid (107D)

Dissolved 107C (84 mg, 0.264 mmol) in 1:1 TFA/CH₂Cl₂ (2 ml). Added 2drops of H₂O and stirred reaction at room temperature for 4 hrs. Thereaction mixture was concentrated in vacuo. The residue was azeotroped2× with Et₂O and then dried under reduced pressure to give 105 mg of thetitle compound.

Synthesis of(S)-5-(2-(1-(2-(2-cyclopentyl-4-(trifluoromethyl)-1H-imidazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(107E)

Prepared 58.5 mg of the title compound by a method analogous to 54Gusing 107D and 54B. ¹H NMR (400 MHz, CD₃OD) δ 8.62 (d, 1H), 7.51 (d,1H), 7.39 (s, 2H), 7.32 (dd, 1H), 7.29-7.22 (m, 1H), 7.18-7.11 (m, 1H),6.60 (s, 1H), 6.29 (d, 2H), 5.26 (t, 1H), 4.71 (d, 2H), 3.05-2.92 (m,2H), 2.87 (s, 1H), 1.69 (s, 8H). MS (m/z) 616 [M+H]⁺.

Example 108

Synthesis of(S)-3-(2-(1-(2-(1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(108)

Prepared 22 mg of the title compound by a method analogous to 50C usingbenzimidazole-1-acetic acid. ¹H NMR (400 MHz, dmso) δ 8.91 (d, 1H), 8.69(dd, 1H), 7.96 (s, 1H), 7.96-7.81 (m, 2H), 7.75-7.59 (m, 3H), 7.53-7.36(m, 3H), 7.27 (q, 2H), 7.07 (t, 1H), 6.93 (t, 1H), 6.51 (d, 2H), 5.18(dd, 2H), 5.04 (s, 2H), 4.59-4.54 (m, 1H), 3.08-2.53 (m, 3H). MS (m/z)512 [M+H]⁺.

Example 109

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-o-tolylpyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(109)

Prepared 16.7 mg of the title compound by a method analogous to 55Fusing 2-methyl-phenylboronic acid and 55E. MS (m/z) 500 [M+H]⁺.

Example 110

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(3-(trifluoromethyl)phenyl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(110)

Prepared 34 mg of the title compound by a method analogous to 55F using3-trifluormethylphenyl boronic acid and 55E. MS (m/z) 554 [M+H]⁺.

Example 111

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(quinolin-3-yl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(1H)

Prepared 22.7 mg of the title compound by analogous method to 55F usingquinoline-3-ylboronic acid and 55E. MS (m/z) 537 [M+H]⁺.

Example 112

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(112B)

Prepared 58.5 mg of the title compound by a method analogous to 54Gusing 112A (prepared by analogous method to 107D) and 54B. ¹H NMR (400MHz, CD₃OD) δ 8.62 (d, 1H), 7.56 (dd, 1H), 7.27 (ddd, 4H), 6.59 (t, 1H),6.26 (d, 2H), 5.28 (t, 1H), 4.56 (s, 2H), 3.79 (t, 2H), 3.08-2.90 (m,2H), 2.78-2.27 (m, 3H). MS (m/z) 605 [M+H]⁺.

Example 113

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-fluorophenyl)pyridin-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(113)

To a solution of 38D (50 mg, 0.103 mmol) and 4-fluorophenyl boronic acid(15.7 mg, 0.113 mmol) in 1 ml DME was added 0.4N aq. K₂CO₃ (515 ul) andPd(PPh₃)₄ (11.9 mg, 0.0010 mmol). The resulting mixture was heated at120° C. for 10 min. under microwave irradiation. Solvents wereconcentrated in vacuo and the residue was purified by RP HPLC using aC18 column with a gradient of 0.1%/H₂O, 0.1% TFA-acetonitrile, toprovide 31 mg of the title compound. ¹H NMR (400 MHz, dmso) δ 10.47 (s,1H), 8.62 (dd, 1H), 8.46 (d, 1H), 7.51 (dd, 1H), 7.34 (dd, 1H), 7.15(dd, 4H), 7.05 (d, 1H), 6.91 (dd, 2H), 6.77 (d, 2H), 6.53 (dd, 1H), 6.34(d, 2H), 5.15 (q, 2H), 4.27-4.22 (m, 1H), 3.39 (s, 2H), 2.90 (d, 2H). MS(m/z) 501 [M+H]⁺.

Example 114

Synthesis of(S)—N-(1-(3-(4-(3-cyclopropylureido)phenyl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(114)

Prepared 12.2 mg of the title compound by a method analogous to 68Busing 68A and 4-(3-cyclopropylureido)phenylboronic acid, pinacol ester.MS (m/z) 655 [M+H]⁺.

Example 115

Synthesis of 4,4-diethoxy-2-(4-methoxyphenyl)butanenitrile (115B)

Compound 115A (21.0 g, 143 mmol) was added to a suspension of NaH (8.9g, 215 mmol) in THF (250 ml), and stirred at 50° C. for 1.5 hr. Ethylbromoacetate (33.82 g, 172 mmol) was added to the mixture which was thenboiled under reflux for 2 hr. The mixture was diluted with water,extracted with EtOAc (400 ml 3) and washed with brine (1000 ml). Thecombined extracts are dried with anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel to afford the title compound (29.2 g, 78% yield) as a paleyellow oil.

Synthesis of 5-ethoxy-3-(4-methoxyphenyl)dihydrofuran-2(3H)-one (115C)

Compound 115B (29.0 g, 110 mmol) and KOH (30.9 g, 550 mmol) aredissolved in EtOH (300 ml) and water (100 ml). The solution was boiledunder reflux for 3 days, acidified with 10 N HCl and evaporated,extracted with EtOAc (400 ml 4) and washed with brine (1500 ml). Thecombined extracts are dried with anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel (PE/EtOAc=8/1) to afford the title compound (14.0 g, 54%yield) as a pale yellow oil.

Synthesis of 4-(4-methoxyphenyl)-1,2-dihydropyridazin-3 (4H)-one (115D)

Compound 115C (3.54 g, 15 mmol) and N₂14-H₂O (2 ml, 30 mmol) aredissolved in AcOH (15 ml) and water (10 ml). The solution was boiledunder reflux for 1.5 hr, and poured into aqueous NaHCO₃, extracted withEtOAc (100 ml 4) and wash with brine (300 ml). The combined extracts aredried with anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography on silica gel (PE/EtOAc=5/1) to affordthe title compound (2.32 g, 72% yield) as a pale yellow solid.

Synthesis of 4-(4-methoxyphenyl)pyridazin-3 (2H)-one (115E)

A solution of Br₂ (0.4 ml) in AcOH (1 ml) was added during 2 min to astirred solution of Compound 115D (1.22 g, 6 mmol) in AcOH (7 ml) at 70°C., which was then poured into aqueous NaHCO₃, extracted with DCM (100ml 4) and wash with brine (400 ml). The combined extracts are dried withanhydrous Na₂SO₄, filtered and concentrated. The residue was purified bycolumn chromatography on silica gel (PE/EtOAc=2/1) to afford the titlecompound (0.89 g, 74% yield) as a yellow solid.

Synthesis of 3-chloro-4-(4-methoxyphenyl)pyridazine (115F)

A solution of Compound 115E (0.89 g, 4.4 mmol, 1.0 eq) in POCl₃ (15 ml)and 3 drops pyridine was boiled under reflux for 3 h. After cooling, thesolution was poured onto ice and extracted with DCM (100 ml 4) and washwith aqueous NaHCO₃ (500 ml) and brine (500 ml). The combined extractsare dried with anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by column chromatography on silica gel (PE/EtOAc=3/1) toafford the title compound (0.69 g, 71% yield) as a pale yellow solid. ¹HNMR (300 MHz, CDCl₃): δ 3.89 (3H, s), 7.05 (2H, d), 7.45 (1H, d), 7.50(2H, d), 9.13 (1H, d); MS (m/z) 613 [M+H]⁺.

Synthesis of 4-(4-methoxyphenyl)pyridazine-3-carbonitrile (115G)

To 115F (395 mg, 1.8 mmol) dissolved in DMF (18 mL) was added Zn(CN)₂(388 mg, 3.3 mmol) and Pd(PPh₃)₄ (50 mg, 0.44 mmol). The mixture wasdegassed by alternating vacuum/N₂ purge (3×) and the reaction heated to100° C. After 2 h, the reaction was cooled to ambient temperature,filtered over celite, and the eluent was concentrated. The residue waspartitioned between EtOAc and H₂O. The organics separated, washed withsaturated aqueous NaCl, and dried. After removal of solvent in vacuo,the residue was purified by column chromatography on silica to provide350 mg of the title compound: ¹H NMR (400 MHz, cdcl₃) δ 9.30 (d, J=5.6Hz, 1H), 7.66-7.57 (m, 3H), 7.24 (s, 1H), 7.12-7.05 (m, 2H), 3.89 (s,3H). MS (m/z) 212.2 [M+H]⁺.

Synthesis of5-(3-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridazin-4-yl)-2-fluorobenzamide(115H)

We envision Compound 115G may be further elaborated to the aminecompound 115H in the manner described for an analogous pyridine compound1B in Example 1. Alternatively, we envision Compound 115G may be furtherelaborated to the amine compound 115H in the manner described for ananalogous pyrazine compound 443B in Example 443

Synthesis of5-(3-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridazin-4-yl)-2-fluorobenzamide(1151)

In a manner analogous to the synthesis of Example 589, we envision thetitle compound may be synthesized utilizing2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidand substituting 115H for 54B.

Example 116 Synthesis of(S)—N-(1-(3-(4-(N,N-diethylsulfamoyl)phenyl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(116)

Prepared 14 mg of the title compound by a method analogous to 68B using68A and 4-(N,N-diethylsulfamoyl)phenylboronic acid. MS (m/z) 692 [M+H]⁺.

Example 117

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(3-fluorophenyl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(117)

Prepared 11.2 mg of the title compound by a method analogous to compound57B using 57A and 3-fluorophenyl boronic acid. MS (m/z) 559 [M+H]⁺.

Example 118

Synthesis of(S)—N-(1-(3-(benzo[d]thiazole-5-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(118)

Prepared 11.1 mg of the title compound by a method analogous to 68Busing 68A and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole. MS(m/z) 612 [M+H]⁺.

Example 119 Synthesis of(S)—N-(1-(3-(4-(N,N-dimethylsulfamoyl)phenyl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(119)

Prepared 17.3 mg of the title compound by a method analogous to 68Busing 68A and 4-(N,N-dimethylsulfamoyl)phenylboronic acid. MS (m/z) 664[M+H]⁺.

Example 120

Synthesis of2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(isoquinolin-4-yl)pyridin-2-yl)ethyl)acetamide(120)

Prepared 6.1 mg of the title compound by a method analogous to 68B using68A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline. MS(m/z) 608 [M+H]⁺.

Example 121

Synthesis of(S)—N-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5-dihydropyrano[3,4-c]pyrazol-1(7H)-yl)acetamide(121)

The title compound was prepared (22 mg) according to the methodpresented in the synthesis of Example 36 utilizing 30E and2-(3-(trifluoromethyl)-4,5-dihydropyrano[3,4-c]pyrazol-1 (7H)-yl)aceticacid. ¹H NMR (400 MHz, dmso) δ 8.95 (s, 1H), 8.61 (s, 1H), 7.50 (s, 1H),7.44-7.28 (m, 3H), 7.19-7.03 (m, 2H), 6.89 (s, 1H), 6.44-6.31 (m, 2H),5.10 (s, 1H), 4.74-4.64 (m, 3H), 4.51-4.30 (m, 4H), 3.72-3.59 (m, 4H),2.95-2.85 (m, 2H), 2.62-2.47 (m, 3H), 2.24 (s, 1H), 1.87-1.76 (m, 1H).MS (m/z) 577.5 [M+H]⁺.

Example 122

Synthesis of bicyclo[3.1.0]hexan-3-one (122B)

To bicyclo[3.1.0]hexan-3-ol (2 g, 20.4 mmol) dissolved in DCM (40 mL)was added NMO (2.99 g, 25.5 mmol) and 4A molecular sieves (˜4 g). Thereaction mixture was cooled to 0° C. and TPAP (144 mg, 2 mol %) added.After 10 min, the reaction was let warm to ambient temperature andstirred for 3 h. The reaction was filtered over celite, eluted with DCMand the eluent purified by column chromatography on silica. The desiredfractions were combined, washed with aqueous 1 N HCl (3×), dried withsodium sulfate, and solvents removed in vacuo to provide the titlecompound.

Synthesis of 2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexan-3-one (122C)

Bicyclo[3.1.0]hexan-3-one (2.18 g, 22.7 mmol) was dissolved in THF (150mL) and cooled to −78° C. upon which LDA (2.0 M, 11.5 mL) was added andstirred 15 min at −78° C. Ethyl 2,2,2-trifluoroacetate (2.96 mL, 25mmol) was added dropwise and the reaction stirred 30 at −78° C. and thenlet warm to room temperature. After 3 h at room temperature, thereaction was judged complete by LCMS. The reaction was quenched withaqueous 1 N HCl and then partitioned between EtOAc and aqueous citricacid. The organics were separated and dried with saturated aqueous NaCl.Solvents were removed in vacuo to provide the title compound (3.74 g).

Synthesis of ethyl2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-2-yl)acetate(122D) and ethyl2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(122E)

2-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexan-3-one (1 g, 5.2 mmol) wasdissolved in EtOH (10 mL) to which sulfuric acid (0.1 mL) was added.2-hydrazinyl acetic acid ethyl ester hydrochloride (0.805 g, 5.2 mmol)was added and the reaction mixture was heated to 85° C. After 30 min,LCMS shows complete conversion to pyrazole product. After cooling toroom temperature, the reaction was neutralized by the addition of 2Naqueous NaOH. The reaction was concentrated in vacuo and the residue waspartitioned between EtOAc and water. The organics were separated, washedwith saturated aqueous NaHCO₃, dried with saturated aqueous NaCl, andsolvents removed in vacuo. NMR indicated the crude product was a mixtureof 122D and the title compound 122E as a ratio of 1:5.5. Theregioisomers were separable by column chromatography on silica toprovide 122D (MS (m/z) 275.1 [M+H]⁺) and the title compound 122E (720mg, MS (m/z) 275.1 [M+H]⁺).

Synthesis of2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (122F)

Ethyl2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(145 mg, 0.53 mmol) was dissolved in a mixture of THF (3 mL) and MeOH (1mL) and treated with LiOH (19 mg, 0.8 mmol) dissolved in H₂O (1 mL).After stirring 3 h at ambient temperature, the mixture was partitionedbetween EtOAc and 20% aqueous KH₂PO₄. The organics were separated,dried, and removed in vacuo to provide the title compound.

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(122G)

Compound 122G was prepared according to the method presented in thesynthesis of Example 54 utilizing 54B and 122F to provide the titlecompound (46 mg): ¹H NMR (400 MHz, dmso) δ 8.91 (d, 1H), 8.66 (s, 1H),7.75-7.56 (m, 3H), 7.49-7.37 (m, 3H), 7.36-7.25 (m, 1H), 6.91 (d, 1H),6.64-6.41 (m, 3H), 5.15 (d, 2H), 4.66 (dd, 3H), 2.99 (t, 2H), 2.64 (s,1H), 2.55 (d, 2H), 2.49-2.42 (m), 2.29 (s, 1H), 2.00 (s, 2H), 1.02 (d,1H), 0.12 (s, 1H). MS (m/z) 600.4 [M+H]⁺.

Example 123

Synthesis of 4,5,6,7-tetrahydro-1H-indazol-3(2H)-one (123B)

Ethyl 2-oxocyclohexanecarboxylate (5 mL, 29.4 mmol) was combined withhydrazine hydrate (1.47 mL, 29.4 mmol) in EtOH (60 mL) and heated toreflux. After 6 h, the reaction was cooled to ambient temperature andwhite precipitate was filtered to obtain pure title compound. MS (m/z)139.13 [M+H]⁺.

Synthesis of tert-butyl2-(3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-1-yl)acetate (123C)

4,5,6,7-Tetrahydro-1H-indazol-3(2H)-one (300 mg, 2.17 mmol) was combinedwith tert-butyl 2-bromoacetate (0.29 mL, 1.96 mmol) and K₂CO₃ (300 mg,2.17 mmol) in acetone/DMF (25 mL, 4:1). The reaction mixture was stirredat 25° C. for 14 h. Multiple isomers were formed in the reaction mixtureand desired product was isolated by column chromatography on silica(yield: 200 mg): MS (m/z) 253.34 [M+H]⁺.

Synthesis of 2-(3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-1-yl)acetic acid(123D)

tert-Butyl 2-(3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-1-yl)acetate (30mg, 0.119 mmol) was dissolved in DCM (0.6 mL) and treated with TFA (0.6mL). The reaction was stirred for 1.5 h at ambient temperature at whichtime solvents were removed in vacuo to provide the desired product: MS(m/z) 197.16 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(123E)

The title compound was prepared (24 mg) according to the methodpresented in the synthesis of Example 54G utilizing 54B and2-(3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-1-yl)acetic acid. ¹H NMR (400MHz, cd₃od) δ 8.69 (dd, 1H), 7.62 (dd, 1H), 7.50 (d, 1H), 7.42 (dd, 1H),7.38-7.17 (m, 2H), 6.75-6.61 (m, 1H), 6.33 (d, 2H), 5.34 (t, 1H), 4.85(s, 11H), 4.66 (d, 2H), 3.29 (dt, 8H), 3.16-2.98 (m, 2H), 2.39 (dt, Hz,3H), 1.99-1.51 (m, 4H), 1.45 (s, 1H). MS (m/z) 550.5 [M+H]⁺.

Example 124

Synthesis of (S)-tert-butyl2-(3,5-difluorophenyl)-1-(5-(quinolin-7-yl)pyrimidin-4-yl)ethylcarbamate(124A)

The title compound as prepared according to the method presented in thesynthesis of 136B in Example 136 utilizing 172A and quinolin-7-ylboronicacid to provide the title compound. MS (m/z) 463.1 [M+H]⁺.

Synthesis of(S)-2-(3,5-difluorophenyl)-1-(5-(quinolin-7-yl)pyrimidin-4-yl)ethanamine(124B)

The title compound as prepared according to the method presented in thesynthesis of 136C in Example 136 utilizing (S)-tert-butyl2-(3,5-difluorophenyl)-1-(5-(quinolin-7-yl)pyrimidin-4-yl)ethylcarbamateto provide the title compound.

Synthesis of2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(5-(quinolin-7-yl)pyrimidin-4-yl)ethyl)acetamide(124C)

The title compound as prepared (20 mg) according to the method presentedin the synthesis of Example 54 utilizing 60G and 124B. ¹H NMR (400 MHz,dmso) δ 9.31 (s, 1H), 9.13 (d, 1H), 8.97 (s, 1H), 8.74 (s, 1H), 8.48 (s,1H), 8.06 (d, 1H), 7.86 (s, 1H), 7.62 (s, 1H), 7.55 (d, 1H), 6.95-6.85(m, 2H), 6.44 (d, 2H), 5.21 (d, 1H), 4.84-4.61 (m, 3H), 3.73 (s, 1H),3.02 (s, 3H), 2.50-2.42 (m), 1.35 (s, 1H), 0.87 (s, 1H). MS (m/z) 609.4[M+H]⁺.

Example 125

Synthesis of(R)—N—((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-5-oxopyrrolidine-2-carboxamide(125)

Compound 140 (6 mg) was dissolved in DCM (3 mL) and treated with TFA (2mL). The reaction was stirred for 3 h at ambient temperature at whichtime solvents were removed in vacuo to provide the title compound (5mg). MS (m/z) 483.4 [M+H]⁺.

Example 126

Synthesis of1-benzoyl-N—((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)pyrrolidine-2-carboxamide(126)

The title compound was prepared (19 mg) according to the methodpresented in the synthesis of Example 54 utilizing 54B and1-benzoylpyrrolidine-2-carboxylic acid. MS (m/z) 573.4 [M+H]⁺.

Example 127

Synthesis of (S)-tert-butyl1-(5-(1H-benzo[d]imidazol-4-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethylcarbamate(127A)

The title compound as prepared according to the method presented in thesynthesis of 68B in Example 68 utilizing 172A and1H-benzo[d]imidazol-4-ylboronic acid to provide the title compound. MS(m/z) 452.2 [M+H]⁺.

Synthesis of(S)-1-(5-(1H-benzo[d]imidazol-4-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethanamine(127B)

The title compound as prepared according to the method presented in thesynthesis of 136C in Example 136 utilizing (S)-tert-butyl1-(5-(1H-benzo[d]imidazol-4-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethylcarbamateto provide the title compound.

Synthesis ofN—((S)-1-(5-(1H-benzo[d]imidazol-4-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(127C)

The title compound as prepared (9 mg) according to the method presentedin the synthesis of Example 54 utilizing 60G and 127B. ¹H NMR (400 MHz,cd₃od) δ 9.36 (s, 1H), 9.20 (s, 1H), 8.72 (s, 1H), 7.90 (d, 1H), 7.65(s, 1H), 6.82 (s, 1H), 6.68 (s, 2H), 6.54 (s, 1H), 6.31 (s, 3H), 4.86(s), 4.77 (s, 3H), 3.29 (dt), 3.06 (d, 3H), 2.97 (s, 1H), 2.84 (s, 1H),2.44 (s, 3H), 1.35 (s, 1H), 1.01 (s, 2H), 0.08 (s, 1H). MS (m/z) 598.3[M+H]⁺.

Example 128

Synthesis of ethyl2-((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamoyl)pyrrolidine-1-carboxylate(128)

The title compound was prepared (9 mg) according to the method presentedin the synthesis of Example 54 utilizing 54B and1-(ethoxycarbonyl)pyrrolidine-2-carboxylic acid.

Example 129

Synthesis of(S)-5-(2-(1-(2-(3-(difluoro(pyridin-2-ylmethoxy)methyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-(pyridin-2-ylmethoxy)benzamide(129)

The title compound was prepared (2 mg) according to the method presentedin the synthesis of Example 159 utilizing 162E and pyridin-2-ylmethanol.¹H NMR (400 MHz, dmso) δ 8.80 (d, J=8.6 Hz, 1H), 8.60 (dd, J=26.7, 10.9Hz, 2H), 8.03 (s, 1H), 7.85 (dd, J=15.6, 7.9 Hz, 1H), 7.71-7.56 (m, 2H),7.50-7.32 (m, 3H), 7.25 (d, J=8.5 Hz, 1H), 6.91 (s, 1H), 6.61 (d, J=6.5Hz, 2H), 5.39 (s, 1H), 5.22 (d, J=6.7 Hz, 1H), 5.00 (s, 1H), 4.63 (d,J=3.4 Hz, 2H), 3.87 (s, 2H), 3.00 (s, 2H), 2.63 (s, 1H), 2.51-2.28 (m,20H), 2.12 (s, 1H), 1.56 (s, 3H). MS (m/z) 780.3 [M+H]⁺.

Example 130

Synthesis of 2-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid(130B)

The title compound was prepared according to the method presented in thesynthesis of 122F in Example 122 utilizing ethyl2-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (synthesized asdescribed in WO 2008/13622).

Synthesis of2-(5-cyclopentenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid(130C)

In a microwave vial,2-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (60 mg, 0.22mmol), cyclopentenylboronic acid (49 mg, 0.44 mmol), Xantphos (13 mg),Pd₂(dba)₃ (10 mg), and 2M aq K₃PO₄ (0.24 mL) were combined in DME (2.2mL). The reaction was heated in a microwave reactor at 180° C. for 40min. The reaction mixture was filtered and solvents removed in vacuo.The residue was partitioned between aqueous saturated NaHCO₃ and EtOAc.The aqueous layer was then acidified with 1N aq HCl and extracted withEtOAc. The organics were washed, dried, and removed in vacuo to providethe title compound. MS (m/z) 573.4 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(5-cyclopentenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(130D)

The title compound was prepared (7 mg) according to the method presentedin the synthesis of Example 54 utilizing 54B and 130C. MS (m/z) 614.4[M+H]⁺.

Example 131

Synthesis of (S)-tert-butyl2-(3,5-difluorophenyl)-1-(5-(isoquinolin-6-yl)pyrimidin-4-yl)ethylcarbamate(131A)

The title compound as prepared according to the method presented in thesynthesis of 136B in Example 136 utilizing 172A andisoquinolin-6-ylboronic acid to provide the title compound. MS (m/z)463.1 [M+H]⁺.

Synthesis of(S)-2-(3,5-difluorophenyl)-1-(5-(isoquinolin-6-yl)pyrimidin-4-yl)ethanamine(131B)

The title compound as prepared according to the method presented in thesynthesis of 136C in Example 136 utilizing (S)-tert-butyl2-(3,5-difluorophenyl)-1-(5-(isoquinolin-6-yl)pyrimidin-4-yl)ethylcarbamateto provide the title compound.

Synthesis of2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(5-(isoquinolin-6-yl)pyrimidin-4-yl)ethyl)acetamide(131C)

The title compound as prepared (26 mg) according to the method presentedin the synthesis of Example 54 utilizing 60G and 131B. ¹H NMR (400 MHz,dmso) δ 9.60 (s, 1H), 9.35 (s, 1H), 9.15 (s, 1H), 8.75 (d, 1H), 8.62 (d,1H), 8.35 (d, 1H), 8.02 (s, 1H), 7.80 (s, 2H), 6.98-6.88 (m, 2H), 6.79(s, 1H), 6.47 (d, 2H), 5.25-5.05 (m, 2H), 4.83-4.63 (m, 4H), 3.05 (d,2H), 2.50-2.41 (m), 1.34 (s, 1H), 0.87 (s, 1H). MS (m/z) 609.4 [M+H]⁺.

Example 132

Synthesis of (2S,4R)-tert-butyl2-((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate(132)

The title compound was prepared (13 mg) according to the methodpresented in the synthesis of Example 54 utilizing 54B and(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid.MS (m/z) 585.1 [M+H]⁺.

Example 133

Synthesis of (R)-tert-butyl3-((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamoyl)morpholine-4-carboxylate(133)

The title compound was prepared (13 mg) according to the methodpresented in the synthesis of Example 54 utilizing 54B and(R)-4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid. ¹H NMR (400MHz, cdcl₃) δ 8.80 (s, 2H), 7.97 (s, 1H), 7.83 (s, 1H), 7.74 (s, 1H),7.54 (s, 1H), 7.37-7.22 (m, 11H), 6.98 (s, 1H), 6.59 (s, 1H), 6.19 (s,4H), 5.57 (s, 1H), 4.55 (s, 1H), 4.39 (s, 1H), 3.71 (d, 3H), 3.63-3.62(m, 1H), 3.45 (s, 1H), 3.24 (s, 2H), 2.50 (s, 1H), 1.46 (s, 5H).

Example 134

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(134)

The title compound was prepared (7 mg) according to the method presentedin the synthesis of Example 56 utilizing 56A and3-(trifluoromethyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole. ¹H NMR (400MHz, dmso) δ 8.94 (d, 1H), 8.67 (s, 1H), 7.72-7.56 (m, 3H), 7.48 (s,1H), 7.45-7.15 (m, 4H), 6.90 (s, 1H), 6.53 (d, 2H), 5.15 (s, 1H), 4.70(s, 2H), 3.00 (s, 2H), 2.55 (s, 2H), 2.51-2.41 (m). MS (m/z) 588.3[M+H]⁺.

Example 135

Synthesis(S)-5-(2-(1-(2-(3-(difluoro(pyridin-2-ylmethoxy)methyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(135)

The title compound was prepared (2 mg) according to the method presentedin the synthesis of Example 159 utilizing 162E and pyridin-2-ylmethanol.The title compound exhibited a shorter retention time on HPLC relativeto its regioisomer (Compound 143). ¹H NMR (400 MHz, dmso) δ 8.86 (d,J=8.3 Hz, 1H), 8.66 (d, J=3.0 Hz, 1H), 8.53 (d, J=5.2 Hz, 1H), 7.83 (d,J=8.2 Hz, 1H), 7.76-7.56 (m, 2H), 7.52-7.21 (m, 4H), 6.91 (s, 1H), 6.55(d, J=6.6 Hz, 2H), 5.17 (d, J=6.6 Hz, 1H), 4.98-4.87 (m, 1H), 4.65 (s,2H), 4.06 (s, 2H), 2.99 (d, J=7.9 Hz, 2H), 2.52-2.41 (m, 18H), 2.39 (s,1H), 2.37-2.30 (m, 1H), 2.22 (d, J=43.0 Hz, 2H), 1.57 (s, 3H). MS (m/z)691.3 [M+H]⁺.

Example 136

Synthesis of (S)-tert-butyl1-(5-(3-carbamoyl-4-fluorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethylcarbamate(136B)

To (S)-tert-butyl1-(5-bromopyrimidin-4-yl)-2-(3,5-difluorophenyl)ethylcarbamate (250 mg,0.6 mmol) in DME (3 mL) was added 3-carbamoyl-4-fluorophenylboronic acid(110 mg, 0.6 mmol), Xantphos (35 mg), Pd₂(dba)₃ (28 mg), and aqueous 2MK₂CO₃ (0.45 mL). The reaction was heated to 65° C. for 2 d at which timeit was diluted with aqueous 1N HCl and extracted with EtOAc. Theorganics were separated, washed, dried and removed in vacuo. The crudeproduct was purified by column chromatography on silica to provide 130mg of the title compound. MS (m/z) 473.0 [M+H]⁺.

Synthesis of(S)-5-(4-(1-amino-2-(3,5-difluorophenyl)ethyl)pyrimidin-5-yl)-2-fluorobenzamide(136C)

(S)-tert-butyl1-(5-(3-carbamoyl-4-fluorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethylcarbamate(130 mg, 0.28 mmol) was dissolved in DCM (2 mL) and treated with HCl (4N in dioxanes, 3 mL). After 3 h at ambient temperature, the solventswere removed in vacuo to provide the title compound.

Synthesis of 5-(4-((1S)-2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyrimidin-5-yl)-2-fluorobenzamide(136D)

The title compound as prepared (16 mg) according to the method presentedin the synthesis of Example 54 utilizing 122F and 136C. ¹H NMR (400 MHz,dmso) δ 9.15 (d, 1H), 8.97 (d, 1H), 8.52 (s, 1H), 7.58 (s, 2H), 7.45(dd, 1H), 7.36 (s, 1H), 7.28-7.20 (m, 1H), 6.83 (d, 1H), 6.48 (t, 2H),5.03 (d, 3H), 4.74-4.40 (m, 4H), 2.50 (ddd, 2H), 2.42-2.20 (m), 1.91 (s,2H), 0.99-0.73 (m, 1H), 0.01 (s, 1H). MS (m/z) 601.2 [M+H]⁺.

Example 137

Synthesis of (S)-tert-butyl2-((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamoyl)-4-oxopyrrolidine-1-carboxylate(137)

The title compound was prepared (12 mg) according to the methodpresented in the synthesis of Example 54 utilizing 54B and(S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid. MS (m/z)583.2 [M+H]⁺.

Example 138

Synthesis of(S)-5-(2-(1-(2-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(138)

The title compound was prepared (43 mg) according to the methodpresented in the synthesis of Example 54 utilizing 54B and 61C. ¹H NMR(400 MHz, dmso) δ 8.96 (d, 1H), 8.71-8.64 (m, 1H), 7.77-7.57 (m, 3H),7.55-7.32 (m, 3H), 7.29 (d, 1H), 6.91 (t, 1H), 6.56 (d, 2H), 6.28 (s,1H), 5.19 (d, 2H), 4.86 (s, 2H), 3.11-2.81 (m, 3H), 2.52-2.42 (m, 20H),1.87 (s, 1H), 1.47 (t, 1H), 0.74 (d, 2H), 0.59 (s, 1H), 0.53 (s, 1H). MS(m/z) 588.6 [M+H]⁺.

Example 139

Synthesis of (2S,5R)-tert-butyl2-((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamoyl)-5-phenylpyrrolidine-1-carboxylate(139)

The title compound was prepared (9 mg) according to the method presentedin the synthesis of Example 54 utilizing 54B and(2S,5R)-1-(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid.MS (m/z) 645.1 [M+H]⁺.

Example 140

Synthesis of (S)-tert-butyl2-((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamoyl)-5-oxopyrrolidine-1-carboxylate(140)

The title compound as prepared (4 mg) according to the method presentedin the synthesis of Example 54 utilizing 54B and(S)-1-(tert-butoxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid. MS (m/z)583.0 [M+H]⁺.

Example 141

Synthesis of 3-methyl-5-(trifluoromethyl)-1H-indazole (141B)

To 1-(2-fluoro-5-(trifluoromethyl)phenyl)ethanone (12.95 g, 62.9 mmol)in ethylene glycol (33 mL) was added hydrazine hydrate (3.1 mL, 100mmol). The reaction was heated at 165° C. for 16 h. After cooling toambient temperature, the reaction solidifies and the solids filtered.The cake was dissolved in DCM, washed with H2O, and dried over sodiumsulfate. Solvents were removed in vacuo to provide 6.75 g of the titlecompound. MS (m/z) 201.0 [M+H]⁺.

Synthesis of tert-butyl3-methyl-5-(trifluoromethyl)-1H-indazole-1-carboxylate (141C)

To 3-methyl-5-(trifluoromethyl)-1H-indazole (3 g, 15 mmol) in THF (100mL) was added Boc₂O (3.27 g, 15 mmol), TEA (2.1 mL, 15 mmol), and DMAP(367 mg, 3 mmol). The reaction was stirred for 2 h then partitionedbetween EtOAc and saturated aqueous NH₄Cl. Organics were separated,dried, and removed in vacuo to provide 3.8 g of the title compound.

Synthesis of tert-butyl3-(bromomethyl)-5-(trifluoromethyl)-1H-indazole-1-carboxylate (141D)

To tert-butyl 3-methyl-5-(trifluoromethyl)-1H-indazole-1-carboxylate(1.9 g) in carbon tetrachloride (20 mL) was added NBS (1.28 g, 7.2mmol). The reaction was heated to 90° C. then AIBN (115 mg, 0.7 mmol)was added. After 16 h, additional aliquots of NBS (500 mg) and AIBN (115mg) were added and the temperature was raised to 110° C. After 16 h, thereaction was cooled to ambient temperature and solvents removed invacuo. The crude residue was partitioned between EtOAc and H₂O. Theorganics were separated, washed with saturated aqueous NaHCO₃, dried,removed in vacuo. The crude product was purified by columnchromatography on silica to provide title compound. MS (m/z) 279.0[M+H]⁺.

Synthesis of 2-(5-(trifluoromethyl)-1H-indazol-3-yl)acetonitrile (141E)

To tert-butyl3-(bromomethyl)-5-(trifluoromethyl)-1H-indazole-1-carboxylate (300 mg,0.79 mmol) dissolved in EtOH (3.5 mL) and H₂O (0.5 mL) was addedcatalytic 18-C-6 and KCN (51 mg, 0.79 mmol). The reaction was stirred 2h then the reaction was partitioned between EtOAc and saturated aqueousNaHCO₃. The organics were separated, washed with, saturated aqueousNaHCO₃ dried and removed in vacuo to provide the title compound. MS(m/z) 226.0 [M+H]⁺.

Synthesis of 2-(5-(trifluoromethyl)-1H-indazol-3-yl)acetic acid (141F)

2-(5-(trifluoromethyl)-1H-indazol-3-yl)acetonitrile (60 mg) was treatedwith 6N aqueous HCl (2 mL) and heated to 105° C. for 5 h. The reactionwas extracted with EtOAc, organics washed with 20% aqueous KH₂PO₄, driedand solvents removed in vacuo to provide 55 mg of the title compound. MS(m/z) 245.0 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-(trifluoromethyl)-1H-indazol-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(141G)

The title compound was prepared (13 mg) according to the methodpresented in the synthesis of Example 54 utilizing 54B and 141F. ¹H NMR(400 MHz, dmso) δ 8.93 (d, 1H), 8.64 (d, 1H), 8.03 (s, 1H), 7.56 (dt,5H), 7.48-7.28 (m, 3H), 7.28-7.17 (m, 1H), 6.82 (s, 1H), 6.47 (d, 2H),5.15 (d, 1H), 3.82 (s, 2H), 2.98 (d, 2H), 2.52-2.41 (m). MS (m/z) 598.4[M+H]⁺.

Example 142

Synthesis of tert-butyl2-(3-(pyrimidin-2-ylmethoxy)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(142A)

tert-Butyl 2-(3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-1-yl)acetate (38mg, 0.15 mmol) was dissolved in DMF (1.5 mL) and treated with2-(chloromethyl)pyrimidine hydrochloride (27 mg, 0.17 mmol) and Cs₂CO₃(196 mg, 0.6 mmol). The reaction mixture was stirred 3 hr. The solidswere filtered and the filtrate partitioned between EtOAc and H₂O. Theorganics were dried over saturated aqueous NaCl and removed in vacuo.The crude residue was purified by column chromatography on silica toprovide a mixture of N1 and N2 regioisomers that were carried onto thenext step: MS (m/z) 345.2 [M+H]⁺.

Synthesis of2-(3-(pyrimidin-2-ylmethoxy)-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid (142B)

The title compound was prepared according to the method presented in thesynthesis of 170B in Example 170: MS (m/z) 289.2 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(pyrimidin-2-ylmethoxy)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(142C)

The title compound was prepared (29 mg) according to the methodpresented in the synthesis of Example 54 utilizing 54B and2-(3-(pyrimidin-2-ylmethoxy)-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid. The undesired N2 isomer observed in the synthesis of 142A wasremoved during purification: ¹H NMR (400 MHz, dmso) δ 8.76 (d, 2H), 8.64(d, 1H), 8.45 (d, 1H), 7.77-7.58 (m, 3H), 7.58-7.27 (m, 5H), 6.90 (s,1H), 6.52 (d, 2H), 5.23-5.12 (m, 3H), 4.34 (s, 2H), 2.94 (dd, 2H),2.53-2.41 (m, 20H), 2.22 (s, 3H), 1.87 (s, 1H), 1.56 (s, 5H). MS (m/z)642.7 [M+H]⁺.

Example 143

Synthesis of(S)-5-(2-(1-(2-(3-(difluoro(pyridin-2-ylmethoxy)methyl)-4,5,6,7-tetrahydro-2H-indazol-2-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(143)

The title compound was prepared (1 mg) according to the method presentedin the synthesis of Example 159 utilizing 162E and pyridin-2-ylmethanol.The title compound exhibited a longer retention time on HPLC relative toits regioisomer (Compound 135). MS (m/z) 691.3 [M+H]⁺.

Example 144

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,5-dihydropyrano[3,4-c]pyrazol-1(7H)-yl)acetamido)ethyl)pyridin-3-yl)benzamide (144)

The title compound was prepared (31 mg) according to the methodpresented in the synthesis of Example 50 utilizing 50C and2-(3-(trifluoromethyl)-4,5-dihydropyrano[3,4-c]pyrazol-1 (7H)-yl)aceticacid. ¹H NMR (400 MHz, dmso) δ 8.99 (d, 1H), 8.68 (s, 1H), 8.01-7.84 (m,2H), 7.71 (s, 1H), 7.64 (d, 1H), 7.45 (dd, 10.1 Hz, 5H), 6.90 (s, 1H),6.48 (d, 2H), 5.19 (s, 1H), 4.75 (s, 2H), 4.48 (d, 2H), 4.39 (d, 2H),3.71 (s, 2H), 3.00 (s, 1H), 2.54 (s, 2H), 2.52-2.42 (m, 68H), 2.29 (s,1H). MS (m/z) 586.4 [M+H]⁺.

Example 145

Synthesis of (2S,4R)-tert-butyl4-(benzyloxy)-2-((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamoyl)pyrrolidine-1-carboxylate(145)

The title compound was prepared (19 mg) according to the methodpresented in the synthesis of Example 54 utilizing 54B and(2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylicacid. ¹H NMR (400 MHz, cdcl₃) δ 9.08 (s, 1H), 8.75 (s, 1H), 7.94 (s,1H), 7.85-7.71 (m, 1H), 7.64 (d, 4H), 7.33-7.23 (m, 1H), 7.23-7.21 (m,1H), 7.08 (s, 1H), 6.59 (s, 1H), 6.33 (s, 1H), 6.28 (d, 3H), 5.54 (s,1H), 4.47 (d, 3H), 4.32 (t, 2H), 4.11 (s, 1H), 3.78 (s, 1H), 3.67 (s,1H), 3.58 (s, 1H), 3.20 (s, 1H), 3.09 (s, 1H), 2.36 (s, 1H), 1.90 (s,1H), 1.41 (s, 8H), 1.23 (s, 4H).

Example 146

Synthesis of(S)—N-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-1-yl)acetamide(146)

The title compound was prepared (14 mg) according to the methodpresented in the synthesis of Example 36 utilizing 36E and 123D. ¹H NMR(400 MHz, cd₃od) δ 8.76-8.36 (m, 1H), 7.61 (dd, 1H), 7.50-7.25 (m, 1H),7.09 (d, 1H)), 6.70 (d, 1H), 6.29 (d, 1H), 5.40 (t, 1H), 5.10 (s, 1H),4.84 (s, 8H), 4.72-4.54 (m, 1H), 3.29 (dt, 8H), 3.10 (d, 1H), 2.99 (d,1H), 2.61 (s, 1H), 2.60-2.16 (m, 2H), 2.24-2.16 (m, 1H), 2.01 (s, 1H),1.76 (d, 2H). MS (m/z) 523.9 [M+H]⁺.

Example 147

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(6-oxo-3-(1H-pyrazol-1-yl)pyridazin-1(6H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide (147)

The title compound was prepared (21 mg) according to the methodpresented in the synthesis of Example 54 utilizing 54B and2-(6-oxo-3-(1H-pyrazol-1-yl)pyridazin-1 (6H)-yl)acetic acid. ¹H NMR (400MHz, dmso) δ 8.94 (d, 1H), 8.71-8.64 (m, 1H), 8.15 (d, 1H), 8.02 (d,1H), 7.80 (d, 1H), 7.71-7.55 (m, 3H), 7.47-7.36 (m, 3H), 7.34-7.20 (m,1H), 7.11 (d, 1H), 6.89 (t, 1H), 6.60-6.42 (m, 3H), 5.16 (d, 1H), 4.63(q, 2H), 3.00 (d, 2H), 2.52-2.41 (m). MS (m/z) 574.3 [M+H]⁺.

Example 148

Synthesis of (2 S,4R)-tert-butyl2-((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamoyl)-4-phenylpyrrolidine-1-carboxylate(148)

The title compound was prepared (16 mg) according to the methodpresented in the synthesis of Example 54 utilizing 54B and(2S,4R)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid.¹H NMR (400 MHz, cdcl₃) δ 9.06 (s, 1H), 8.76 (s, 1H), 7.98 (s, 1H), 7.72(s, 2H), 7.63 (s, 1H), 7.44-7.14 (m, 3H), 6.58 (s, 1H), 6.27 (d, J=22.0Hz, 3H), 5.64 (s, 1H), 4.40 (s, 1H), 4.01 (s, 1H), 3.32 (s, 3H), 3.21(s, 2H), 2.25 (s, 3H), 1.45 (s, 7H), 1.28 (s, 3H). MS (m/z) 645.1[M+H]⁺.

Example 149

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(2-phenyl-1H-imidazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(149)

The title compound was prepared (7 mg) according to the method presentedin the synthesis of Example 54 utilizing 54B and2-(2-phenyl-1H-imidazol-1-yl)acetic acid. ¹H NMR (400 MHz, dmso) δ 9.13(d, 1H), 8.69 (d, 1H), 7.74 (s, 1H), 7.72-7.49 (m, 6H), 7.50 (s, 1H),7.56-7.39 (m, 6H), 7.31 (d, 2H), 6.95 (s, 1H), 6.51 (d, 2H), 5.11 (d,1H), 4.85 (s, 3H), 2.95 (dd, 2H), 2.52-2.41 (m, 38H). MS (m/z) 556.6[M+H]⁺.

Example 150

Synthesis of(S)-5-(2-(1-(2-(5,5-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(150)

In a plastic bottle, 446 (15 mg, 0.024 mmol) was dissolved in DCM (0.10mL) and treated with Deoxo-Fluor (25 μL). After 15 min at ambienttemperature, the reaction was quenched with aqueous saturated NaHCO₃ andextracted with DCM. The organics evaporated and the residue was purifiedby RP HPLC to provide the desired compound (3 mg). ¹⁹F NMR (376 MHz,cdcl₃) δ −62.32, −76.30, −98.50, −109.31. MS (m/z) 638.2 [M+H]⁺.

Example 151

Synthesis of 2-(2,2,2-trifluoroacetyl)cyclopentanone (151B)

The title compound was prepared according to the method presented in thesynthesis of 122C in Example 122 utilizing cyclopentanone

Synthesis of ethyl2-(3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)acetate(151C)

The title compound was prepared according to the method presented in thesynthesis of 122D in Example 122 utilizing2-(2,2,2-trifluoroacetyl)cyclopentanone. The title compound was theexclusive product of this reaction. MS (m/z) 263.1 [M+H]⁺.

Synthesis of2-(3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)aceticacid (151D)

The title compound was prepared according to the method presented in thesynthesis of 122F in Example 122 utilizing ethyl2-(3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)acetate.MS (m/z) 235.0 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(151E)

The title compound was prepared (8 mg) according to the method presentedin the synthesis of Example 54 utilizing 54B and 151D. ¹H NMR (400 MHz,dmso) δ 8.79 (d, 1H), 8.67 (d, 1H), 7.73-7.57 (m, 3H), 7.40 (dt, 3H),7.30 (s, 1H), 6.91 (s, 1H), 6.54 (d, 2H), 5.14 (s, 1H), 4.72 (s, 2H),2.98 (s, 2H), 2.63-2.52 (m, 4H), 2.52-2.41 (m), 2.30 (s, 2H). MS (m/z)588.3 [M+H]⁺.

Example 152

Synthesis of2-(5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)acetonitrile (152B)

To 2-(chloromethyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline(synthesized as described in US 2007/0032469) (700 mg, 3.39 mmol)dissolved in EtOH (12 mL)/H₂O (1.2 mL) was added 18-C-6 (catalyticamount) and KCN (220 mg, 3.39 mmol). The reaction was heated to 50° C.for 3 h. Solvents were removed in vacuo and the residue was purified bycolumn chromatography on silica to provide the title compound. MS (m/z)198.1 [M+H]⁺.

Synthesis of 2-(5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)aceticacid (152C)

2-(5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)acetonitrile (90 mg,0.45 mmol) was dissolved in 6 N HCl (3 mL) and heated to 70° C. After 1h, the reaction temperature was raised to 105° C. After 2 h, thereaction was cooled to 0° C., neutralized with 20% aqueous NaOH, andbuffered with 20% aqueous KH₂PO₄. The product was water soluble andunable to extract into organic solvents. The aqueous solution wasremoved in vacuo and crude product was directly used in the nextreaction. MS (m/z) 217.1 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(152D)

The title compound (4 mg) was prepared according to the method presentedin the synthesis of Example 54G utilizing 54B and2-(5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)acetic acid. ¹H NMR(400 MHz, cd₃od) δ 8.60 (d, 1H), 7.52-7.45 (m, 1H), 7.37 (d, 1H),7.31-7.23 (m, 1H), 7.21 (s, 1H), 7.15-6.98 (m, 2H), 6.91 (d, 1H), 6.54(t, 1H), 6.26 (d, 2H), 5.28 (t, 1H), 4.75 (s, 19H), 3.98 (s, 2H), 3.83(s, 1H), 3.24 (s, 1H), 3.38-2.92 (m, 23H), 2.86 (t, 2H), 2.30-1.90 (m,2H). MS (m/z) 570.4 [M+H]⁺.

Example 153

Synthesis ofN—((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-1-(cyclopentanecarbonyl)pyrrolidine-2-carboxamide(153)

The title compound was prepared (6 mg) according to the method presentedin the synthesis of Example 54 utilizing 54B and1-(cyclopentanecarbonyl)pyrrolidine-2-carboxylic acid. ¹H NMR (400 MHz,cdcl₃) δ 8.78 (s, 1H), 8.71 (s, 1H), 8.02 (s, 1H), 7.75 (s, 2H), 7.61(s, 1H), 7.31 (s, 1H), 6.59 (s, 1H), 6.28 (d, J=6.2 Hz, 2H), 6.06 (s,1H), 5.61 (s, 1H), 4.33 (s, 1H), 3.95 (s, 1H), 3.55 (s, 1H), 3.28 (d,J=28.6 Hz, 2H), 3.03 (s, 1H), 2.13 (s, 6H), 1.93 (s, 6H), 1.61 (d,J=43.1 Hz, 6H).

Example 154, 155, and 156

Synthesis of5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(154)

The title compound was prepared according to the method presented in thesynthesis of 325B in Example 325 utilizing 561B. Purification of thecrude mixture by RP HPLC resulted in isolation of three peaks. Compound154 (3.5 mg) is the peak with the shortest retention time. ¹H NMR (400MHz, cd₃cn) δ 8.58 (dd, 1H), 8.17 (s, 1H), 7.70 (dd, 1H), 7.65-7.43 (m,2H), 7.26 (s, 1H), 7.17 (dd, 1H), 6.77 (s, 1H), 6.61 (t, 1H), 6.27 (t,3H), 5.34-5.21 (m, 2H), 4.61 (q, 2H), 3.32 (s, 2H), 2.94 (qd, 3H),2.30-1.90 (m, 3H), 1.85 (dt), 0.89 (td, 1H), 0.72 (dd, 1H). MS (m/z)616.1 [M+H]⁺.

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(155)

The title compound was prepared according to the method presented in thesynthesis of 325B in Example 325 utilizing 561B. Purification of thecrude mixture by RP HPLC resulted in isolation of three peaks. Compound155 (5 mg) is the peak with second shortest retention time and is amixture of diastereomers. ¹H NMR (400 MHz, cd₃cn) δ 8.57-8.45 (m, 1H),7.68 (dd, 1H), 7.66-7.41 (m, 2H), 7.41-7.06 (m, 3H), 7.06-7.03 (m, 1H),6.61 (d, 2H), 6.50 (d, 1H), 6.33-5.90 (m, 4H), 5.27-5.06 (m, 2H),4.64-4.47 (m, 2H), 3.62 (s, 6H), 3.17-2.66 (m, 3H), 1.96 (ddd, 3H), 1.75(dt), 1.09-0.87 (m, 1H), 0.78 (dd, 1H), 0.61 (d, 11-), 0.02 (dd, J=8.3,4.7 Hz, 1H). MS (m/z) 616.1 [M+H]⁺.

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(156)

The title compound was prepared according to the method presented in thesynthesis of 325B in Example 325 utilizing 561B. Purification of thecrude mixture by RP HPLC resulted in isolation of three peaks. Compound156 (4 mg) is the peak with longest retention time and is a mixture ofdiastereomers. ¹H NMR (400 MHz, cd₃cn) δ 8.68 (d, 1H), 7.73 (s, 1H),7.63 (s, 1H), 7.51 (s, 1H), 7.36-7.23 (m, 2H), 6.90 (s, 1H), 6.69 (s,1H), 6.34 (d, 4H), 5.34 (d, 2H), 4.74 (dd, 2H), 3.00 (d, 3H), 2.16 (s,1H), 1.95 (dt), 1.20 (s, 1H), 0.97 (d, 1H), 0.75 (d, 11-H), 0.22 (s,1H). MS (m/z) 616.1 [M+H]⁺.

Example 157

Synthesis of(2S,4R)-4-(benzyloxy)-N—((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)pyrrolidine-2-carboxamide(157)

The title compound was prepared (9 mg) according to the method presentedin the synthesis of Example 125 utilizing 145. MS (m/z) 575.4 [M+H]⁺.

Example 158

Synthesis of (2R,5S)-tert-butyl2-((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamoyl)-5-phenylpyrrolidine-1-carboxylate(158)

The title compound was prepared (6 mg) according to the method presentedin the synthesis of Example 54 utilizing 54B and(2R,5S)-1-(tert-butoxycarbonyl)-5-phenylpyrrolidine-2-carboxylic acid.¹H NMR (400 MHz, cdcl₃) δ 8.74 (d, 1H), 8.6 (m, 1H) 7.86 (s, 1H), 7.62(d, 2H), 7.33-7.22 (m, 10H), 6.59 (s, 1H), 6.19 (d, 2H), 6.06 (s, 1H),5.48 (s, 1H), 4.59 (d, 1H), 3.11 (s, 1H), 3.02 (s, 1H), 2.53 (s, 2H),2.43 (s, 2H), 1.86 (s, 1H), 1.41 (s, 10H). MS (m/z) 645.1 [M+H]⁺.

Example 159

Synthesisof(S)-5-(2-(1-(2-(3-(difluoro(phenoxy)methyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(159)

(S)-5-(2-(1-(2-(3-(chlorodifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(36 mg, 0.06 mmol) was dissolved in THF (0.6 mL) and treated with KHMDS(2.7 mg, 0.14 mmol). Phenol (14 mg, 0.15 mmol) was added to the reactionmixture the temperature was raised to 45° C. After stirring for 16 h,solvent were removed in vacuo. The residue was purified by RP HPLC toprovide the title compound (7 mg) as a mixture with its regioisomer((S)-5-(2-(1-(2-(3-(difluoro(phenoxy)methyl)-4,5,6,7-tetrahydro-2H-indazol-2-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide:¹H NMR (400 MHz, dmso) δ 8.88 (d, 1H), 8.81-8.59 (m, 2H), 7.84-7.55 (m,4H), 7.55-7.14 (m, 8H), 7.10 (d, 1H), 7.05-6.81 (m, 1H), 6.56 (d, 2H),6.47 (d, 1H), 5.22-5.12 (m, 1H), 4.84 (s, 2H), 4.74 (d, 16H), 3.18-2.72(m, 3H), 2.52-2.42 (m, 12H), 2.25 (d, 1H), 1.60 (s, 6H). MS (m/z) 676.2[M+H]⁺.

Example 160

Synthesis of 5-(2-((1S)-1-(2-(3-(difluoromethyl)-4,4a,5,5a-tetrahydro-2H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-2-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(160)

The title compound was prepared (8 mg) according to the method presentedin the synthesis of Example 56 utilizing 56A and 163B to provide toregioisomeric products. The title compound was the minor product (8 mg):¹H NMR (400 MHz, dmso) δ 8.63 (t, 1H), 8.53 (d, 1H), 7.47 (dd, 3H),7.41-7.19 (m, 3H), 7.19-7.09 (m, 1H), 6.85 (s, 1H), 6.80-6.69 (m, 1H),6.58 (d, 1H), 6.36 (d, 2H), 5.00 (d, 1H), 4.55 (s, 2H), 2.84 (t, 2H),2.62 (d, 2H), 2.44 (d, 1H), 2.34 (s, 3H), 2.34-1.72 (m), 0.93 (d, 1H),0.00 (d, J=4.0 Hz, 2H). MS (m/z) 582.2 [M+H]⁺.

Example 161

Synthesis of (2S,4S)-tert-butyl2-((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamoyl)-4-phenoxypyrrolidine-1-carboxylate(161)

The title compound as prepared (12 mg) according to the method presentedin the synthesis of Example 54 utilizing 54B and(2S,4S)-1-(tert-butoxycarbonyl)-4-phenoxypyrrolidine-2-carboxylic acid.MS (m/z) 661.3 [M+H]⁺.

Example 162

Synthesis of 2-(2-chloro-2,2-difluoroacetyl)cyclohexanone (162B)

The title compound was prepared according to the method presented in thesynthesis of 122C in Example 122 utilizing cyclohexanone and ethyl2-chloro-2,2-difluoroacetate

Synthesis of 3-(chlorodifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole(162C)

The title compound was prepared according to the method presented in thesynthesis of 169D in Example 169 utilizing2-(2-chloro-2,2-difluoroacetyl)cyclohexanone. MS (m/z) 207.4 [M+H]⁺

Synthesis of2-(3-(chlorodifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid (162D)

In a microwave vial,3-(chlorodifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (580 mg, 2.81mmol) was combined with tert-butyl 2-bromoacetate (2.5 mL, 17 mmol), KI(166 mg), and 18-C-6 (catalytic) in NMP (2.8 mL). The reaction mixturewas heated in a microwave reactor at 120° C. for 90 min. The reactionwas partitioned between EtOAc and saturated aqueous NaCl. The organicswere separated, dried and removed in vacuo. The residue was purified bycolumn chromatography on silica to provide the title compound as a 1.5:1mixture with its regioisomer2-(3-(chlorodifluoromethyl)-4,5,6,7-tetrahydro-2H-indazol-2-yl)aceticacid. MS (m/z) 265.1 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(3-(chlorodifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(162E)

The title compound was prepared according to the method presented in thesynthesis of Example 54 utilizing 162D. The title compound (5 mg) wasnot able to be purified from the regioisomer((S)-5-(2-(1-(2-(3-(chlorodifluoromethyl)-4,5,6,7-tetrahydro-2H-indazol-2-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide)and was tested as a mixture. ¹H NMR (400 MHz, cd₃od) δ 8.68 (s, 1H),7.60 (s, 1H), 7.36 (d, J=22.1 Hz, 3H), 7.21 (s, 1H), 6.66 (s, 1H), 6.32(s, 2H), 5.36 (s, 2H), 3.03 (s, 2H), 2.62 (s, 3H), 2.44 (s, 2H), 1.76(s, 4H). MS (m/z) 618.7 [M+H]⁺.

Example 163

Synthesis of 3-(2,2-difluoroacetyl)bicyclo[3.1.0]hexan-2-one (163A)

The title compound was prepared according to the method presented in thesynthesis of 122C in Example 122 utilizing 169B and ethyl2,2-difluoroacetate

Synthesis of3-(difluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazole(163B)

The title compound was prepared according to the method presented in thesynthesis of 169D in Example 169 utilizing 163A. MS (m/z) 171.0 [M+H]⁺.

Synthesis of 5-(2-((1S)-1-(2-(3-(difluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(163C)

The title compound was prepared according to the method presented in thesynthesis of Example 56 utilizing 56A and 163B to provide toregioisomeric products. The title compound was the major product (6 mg):¹H NMR (400 MHz, dmso) δ 8.67 (d, 1H), 8.47 (d, 1H), 7.57-7.35 (m, 3H),7.35-7.16 (m, 3H), 7.16-7.01 (m, 1H), 6.69 (dd, 2H), 6.48 (s, 1H), 6.35(d, 3H), 5.23-4.92 (m, 2H), 4.74-4.39 (m, 4H), 3.90 (s, 1H), 2.80 (d,3H), 2.65-2.33 (m, 3H), 2.32 (s, 1H), 2.30-2.22 (m), 1.81 (d, 5H), 0.77(dd, 2H), 0.00 (d, 1H). MS (m/z) 582.2 [M+H]⁺.

Example 164

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-phenoxyacetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(164)

Under the conditions described in Example 159, the title compound wasisolated as side product (2 mg): ¹H NMR (400 MHz, dmso) δ 8.66 (dd, 1H),8.57 (d, 1H), 7.87-7.58 (m, 4H), 7.54 (s, 1H), 7.54-7.28 (m, 4H),7.28-7.15 (m, 2H), 6.90 (dd, 2H), 6.78 (d, 2H), 6.55 (d, 2H), 5.21 (d,2H), 4.41 (s, 3H), 3.79 (bs), 3.17-2.90 (m, 3H), 2.52-2.41 (m, 14H). MS(m/z) 506.4 [M+H]⁺.

Example 165

Synthesis of(2S,4S)—N—((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-4-phenoxypyrrolidine-2-carboxamide(165)

The title compound was prepared (3 mg) according to the method presentedin the synthesis of Example 125 utilizing 161.

Example 166

Synthesis of1-benzyl-N—((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)pyrrolidine-2-carboxamide(166)

The title compound was prepared (31 mg) according to the methodpresented in the synthesis of Example 54 utilizing 54B and1-benzylpyrrolidine-2-carboxylic acid. MS (m/z) 559.4 [M+H]⁺.

Example 167

Synthesis of(S)—N—((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-4-oxopyrrolidine-2-carboxamide(167)

The title compound was prepared (5 mg) according to the method presentedin the synthesis of Example 125 utilizing 137. MS (m/z) 483.4 [M+H]⁺.

Example 168

Synthesis of 2-(5-cyclopentyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)aceticacid (168A)

To 130C (30 mg, 0.11 mmol) dissolved in EtOH (4 mL) was added Pd/C (5mg) and placed under an atmosphere of H₂. The reaction was stirred for16 h then filtered over celite. The eluent was removed in vacuo. MS(m/z) 263.1 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(5-cyclopentyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(168B)

The title compound was prepared (5 mg) according to the method presentedin the synthesis of Example 54 utilizing 54B and 168A. ¹H NMR (400 MHz,dmso) δ 8.92 (d, 1H), 8.67 (d, 1H), 7.67-7.58 (m, 3H), 7.53-7.31 (m,4H), 7.29 (d, 1H), 6.92 (s, 1H), 6.57 (d, 2H), 6.44 (s, 1H), 5.17 (d,2H), 4.80 (q, 4H), 3.01 (t, 2H), 2.72 (t, 1H), 2.52-2.41 (m), 1.77 (s,1H), 1.77-1.66 (m, 1H), 1.54 (d, 4H), 1.37 (d, 1H). MS (m/z) 616.4[M+H]⁺.

Example 169

Synthesis of bicyclo[3.1.0]hexan-2-one (169B)

The title compound was prepared according to the method presented in thesynthesis of 122B in Example 122 utilizing bicyclo[3.1.0]hexan-2-ol(synthesized as described in J. Am. Chem. Soc 2004, 126, 8664-8665).

Synthesis of 3-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexan-2-one (169C)

The title compound was prepared according to the method presented in thesynthesis of 122C in Example 122 utilizing bicyclo[3.1.0]hexan-2-one

Synthesis of3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazole(169D)

To 3-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexan-2-one (290 mg, 1.5 mmol)dissolved in EtOH (14 mL) was added hydrazine hydrate (2 mmol) andheated to 85° C. After 16 hours, the reaction was cooled to ambienttemperature and solvents removed in vacuo. The residue was partitionedbetween EtOAc and H₂O. The organics were separated, dried and removed invacuo. The crude product was purified by column chromatography on silicato provide the title compound. MS (m/z) 189.0 [M+H]⁺.

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(169E)

The title compound was prepared (14 mg) according to the methodpresented in the synthesis of Example 56 utilizing 56A and 169D. MS(m/z) 600.3 [M+H]⁺.

Example 170

Synthesis of tert-butyl2-(2-ethyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-1-yl)acetate (170A)

tert-Butyl 2-(3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-1-yl)acetate (52mg, 0.21 mmol) was dissolved in acetone (2 mL) and treated with EtI (18μL, 0.23 mmol) and K₂CO₃ (34 mg, 0.23 mmol). DMF (1 mL) was added to aidsolubility and the reaction was heated to 50° C. for 14 hr. Twoalkylation regioisomers were obtained. The title compound was the minorregioisomer exhibiting a longer retention time on HPLC: MS (m/z) 281.1[M+H]⁺.

Synthesis of2-(2-ethyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-1-yl)acetic acid(170B)

tert-Butyl2-(2-ethyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-1-yl)acetate (0.1mmol) was dissolved in DCM (1 mL) and treated with TFA (1 mL). Thereaction was stirred for 2 h at ambient temperature at which timesolvents were removed in vacuo to provide the desired product: MS (m/z)225.2 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(2-ethyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(170C)

The title compound was prepared (14 mg) according to the methodpresented in the synthesis of Example 54 utilizing 54B and2-(2-ethyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-1-yl)acetic acid. ¹HNMR (400 MHz, cd₃od) δ 8.73-8.66 (m, 1H), 7.63-7.55 (m, 1H), 7.50 (d,1H), 7.32 (ddd, 3H), 6.69 (s, 1H), 6.37 (d, 2H), 5.31 (t, 1H), 4.83 (s,20H), 4.72-4.58 (m, 3H), 4.12 (d, 1H), 4.01-3.67 (m, 3H), 3.29 (dt,29H), 3.04 (t, 4H), 2.79 (s, 1H), 2.45 (d, 2H), 2.35 (d, 4H), 1.78 (s,3H), 1.71 (s, 3H), 1.31 (t, 1H), 1.12 (t, 3H). MS (m/z) 578.5 [M+H]⁺.

Example 171

Synthesis of (S)-tert-butyl2-((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylcarbamoyl)pyrrolidine-1-carboxylate(171)

The title compound was prepared (6 mg) according to the method presentedin the synthesis of Example 54 utilizing 54B and(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid. MS (m/z) 569.2[M+H]⁺.

Example 172

Synthesis of (S)-tert-butyl1-(5-bromopyrimidin-4-yl)-2-(3,5-difluorophenyl)ethylcarbamate (172A)Synthesis of (S)-tert-butyl 1-(5-(IH-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethylcarbamate(172B)

The title compound as prepared according to the method presented in thesynthesis of 136B in Example 136 utilizing 172A and1H-pyrrolo[2,3-b]pyridin-5-ylboronic acid to provide the title compound.MS (m/z) 451.8 [M+H]⁺.

Synthesis of(S)-1-(5-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethanamine(172C)

The title compound as prepared according to the method presented in thesynthesis of 136C in Example 136 utilizing (S)-tert-butyl1-(5-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethylcarbamateto provide the title compound.

Synthesis ofN—((S)-1-(5-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(172D)

The title compound as prepared (4 mg) according to the method presentedin the synthesis of Example 54 utilizing 60G and 172C. ¹H NMR (400 MHz,cd₃cn) δ 12.37 (s, 1H), 9.26 (s, 1H), 8.59 (s, 1H), 8.20 (d, 1H), 8.08(d, 1H), 7.70 (s, 1H), 7.42 (s, 3H), 6.89 (d, 1H), 6.74 (dd, 2H), 6.62(d, 1H), 6.37 (d, 2H), 5.30 (d, 1H), 4.74 (p, 2H), 3.02 (t, 2H), 2.48(s, 2H), 1.95 (dt), 1.39 (dd, 1H), 1.01 (s, 1H). MS (m/z) 598.1 [M+H]⁺.

Examples 173 and 174

Synthesis of5-(2-((S)-2-(3,5-difluorophenyl)-1-(2-((3bR,4aR)-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamideand5-(2-((S)-2-(3,5-difluorophenyl)-1-(2-((3bS,4aS)-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(173 and 174)

The title compounds were separated from the diastereomeric mixture 122Fby semi-preparative chiral HPLC fitted with a Chiralpak IC columnrunning a 70:30 mixture of Hep:IPA to obtain the desired compounds aspure diastereomers: 173 (14 mg): HPLC rt=11.5 min; MS (m/z) 600.4[M+H]⁺. 174 (12 mg): HPLC rt=13.5 min; MS (m/z) 600.4 [M+H]⁺. Absolutestereochemistry is unknown.

Example 175

Synthesisof(S)—N—((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)pyrrolidine-2-carboxamide(175)

The title compound was prepared (4 mg) according to the method presentedin the synthesis of Example 125 utilizing 171. MS (m/z) 469.4 [M+H]⁺.

Example 176

Synthesis of (S)-tert-butyl1-(5-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethylcarbamate(176A)

The title compound as prepared according to the method presented in thesynthesis of 136B in Example 136 utilizing 172A and1H-pyrazolo[3,4-b]pyridin-5-ylboronic acid to provide the titlecompound. MS (m/z) 452.8 [M+H]⁺.

Synthesis of(S)-1-(5-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethanamine(176B)

The title compound as prepared according to the method presented in thesynthesis of 136C in Example 136 utilizing (S)-tert-butyl1-(5-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethylcarbamate to provide the title compound.

Synthesis ofN—((S)-1-(5-(1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(176C)

The title compound as prepared (2 mg) according to the method presentedin the synthesis of Example 54 utilizing 60G and 176B. ¹H NMR (400 MHz,cd₃cn) δ 9.23 (s, 1H), 8.58 (d, 1H), 8.29 (s, 1H), 8.10 (d, 1H), 7.88(d, 1H), 7.37 (d, 1H), 6.89 (d, —1H), 6.73 (dd, 2H), 6.62 (d, 1H), 6.33(d, 2H), 5.33 (q, 1H), 4.87-4.65 (m, 3H), 2.99 (dd, 3H), 2.48 (s, 2H),1.95 (dt), 1.39 (dd, 1H), 1.01 (s, 1H). MS (m/z) 599.0 [M+H]⁺.

Example 177

Synthesis of (2S,4R)—N—((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-4-phenylpyrrolidine-2-carboxamide(177)

The title compound was prepared (11 mg) according to the methodpresented in the synthesis of Example 125 utilizing 148. MS (m/z) 545.2[M+H]⁺.

Example 178

Synthesis of(2S,4R)—N—((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide(178)

The title compound was prepared (10 mg) according to the methodpresented in the synthesis of Example 125 utilizing 132. MS (m/z) 485.4[M+H]⁺.

Example 179

Synthesis of tert-butyl2-(3-ethoxy-4,5,6,7-tetrahydro-H-indazol-1-yl)acetate (179A)

Under the conditions described for the synthesis of 170A in Example 170,the title compound was synthesized as the major regioisomer exhibiting ashorter retention time on HPLC: MS (m/z) 281.1 [M+H]⁺.

Synthesis of 2-(3-ethoxy-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid(179B)

The title compound was prepared according to the method presented in thesynthesis of 170B in Example 170: MS (m/z) 225.2 [M+H]⁺

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-ethoxy-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(179C)

The title compound was prepared (70 mg) according to the methodpresented in the synthesis of Example 54 utilizing 54B and2-(3-ethoxy-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid. ¹H NMR (400MHz, cd₃od) δ 8.66 (dd, 1H), 7.68 (dd, 1H), 7.56-7.43 (m, 2H), 7.34 (s,1H), 7.25 (dd, 1H), 6.67 (t, 1H), 6.32 (d, 2H), 5.38 (t, 1H), 4.84 (s,10H), 4.52 (s, 2H), 4.14 (q, 2H), 3.29 (dt, 9H), 2.99 (d, 2H), 2.34 (dt,4H), 1.78-1.64 (m, 4H), 1.33 (t, 3H). MS (m/z) 578.7 [M+H]⁺.

Example 180

Synthesis of5-(4-((1S)-1-(2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyrimidin-5-yl)-2-fluorobenzamide(180)

The title compound as prepared (51 mg) according to the method presentedin the synthesis of Example 54 utilizing 60G and 136C. ¹H NMR (400 MHz,dmso) δ 9.25 (s, 1H), 9.11 (s, 1H), 8.62 (s, 1H), 7.66 (s, 2H), 7.52 (s,1H), 7.36 (d, 1H), 6.92 (s, 2H), 6.59 (s, 2H), 5.11 (s, 1H), 4.70 (d,3H), 3.37 (bs), 3.00 (d, 3H), 2.51-2.42 (m), 1.33 (s, 1H), 0.87 (s, 1H).MS (m/z) 619.3 [M+H]⁺.

Example 181

Synthesis of ethyl2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(181A)

Ethyl2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(1.92 g, 7 mmol) and celite 545 (1 g/mmol) was combined in benzene (50mL) and cooled to 5° C. (just above freezing). PDC (10.5 g, 28 mmol) wasadded followed by tert-butylhydroperoxide (5-6 M solution in decane, 5.1mL, 28 mmol). The solution was let warm to ambient temperature, thenstirred for 3 days. The reaction is filtered over celite, eluted withEtOAc, and the solvents removed in vacuo. Crude residue is resubjectedto the same reaction conditions and let stir for 1 day. The reaction isagain filtered over celite, eluted with EtOAc, and the solvents removedin vacuo to provide the title compound (1.1 g) as a mixture with 122D(ratio determined by 19F NMR): MS (m/z) 289.0 [M+H]⁺.

Synthesis of ethyl2-(3-(trifluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2′-[1,3]dithiolane]-1(3bH)-yl)acetate (181B)

Ethyl2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(1.1 g, 3.8 mmol) and ethanediol (0.54 mL, 6.4 mmol) were combined inDCM (12 mL) to which BF₃ acetic acid complex (0.88 mL, 6.4 mmol) wasadded. The reaction was stirred at ambient temperature for 3 h. LCMSshows complete conversion of keto-starting material to product. Thereaction was cooled to 0° C. and quenched with saturated aqueous NaHCO₃.The organics were separated and dried with saturated aqueous NaCl.Solvents were removed in vacuo and the residue purified by columnchromatography on silica to provide 900 mg of the title compound productas a mixture with compound 122D. MS (m/z) 365.1 [M+H]⁺.

Synthesis of ethyl2-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(181C)

In a teflon bottle, NIS (1.34 g, 5.93 mmol) was suspended in DCM (1.5mL) and cooled to −78° C. HF pyridine (4 mL) added. Ethyl2-(3-(trifluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2′-[1,3]dithiolane]-1(3bH)-yl)acetate was dissolved in DCM (2.5 mL) and added dropwise. Thereaction was stirred 30 min at −78° C. then let slowly warm to −30° C.The reaction was held at −30 OC for 3 h. To a 1 L beaker charged withsaturated aqueous NaHCO₃ (100 mL), ice was added to increase volume to250 ml and stirred vigorously. The reaction was poured into the basicquench solution. The solution was extracted with EtOAc (3×), organicsseparated and dried with saturated aqueous NaCl. Solvents were removedin vacuo and the residue purified by column chromatography on silica toprovide the title compound (320 mg): MS (m/z) 311.0 [M+H]⁺.

Synthesis of2-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (181D)

The title compound was prepared according to the method presented in thesynthesis of 122F in Example 122 utilizing 181C. MS (m/z) 283.0 [M+H]⁺.

Synthesis of 5-(2-((1S)-1-(2-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(181E)

The title compound (10 mg) was prepared according to the methodpresented in the synthesis of Example 54 utilizing 54B and 181D. ¹H NMR(400 MHz, dmso) δ 8.97 (s, 1H), 8.67 (d, 1H), 7.75-7.57 (m, 3H), 7.41(dd, 2H), 7.35-7.24 (m, 1H), 6.88 (s, 1H), 6.53 (s, 2H), 5.14 (s, 1H),4.77 (dt, 4H), 3.88 (bs), 2.98 (d, 2H), 2.51-2.42 (m), 1.36 (s, 1H),0.96 (s, 1H). MS (m/z) 636.1 [M+H]⁺.

Example 182

Synthesis of(2S,5R)—N—((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-5-phenylpyrrolidine-2-carboxamide(182)

The title compound was prepared (3 mg) according to the method presentedin the synthesis of Example 125 utilizing 139. MS (m/z) 545.3 [M+H]⁺.

Example 183 Synthesis of(2R,5S)—N—((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-5-phenylpyrrolidine-2-carboxamide(183)

The title compound was prepared (3 mg) according to the method presentedin the synthesis of Example 125 utilizing 158. MS (m/z) 545.3 [M+H]⁺.

Example 184

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-methyl-3-phenyl-1H-pyrazol-4-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(184)

The title compound was prepared (9 mg) according to the method presentedin the synthesis of Example 54 utilizing 54B and2-(5-methyl-3-phenyl-1H-pyrazol-4-yl)acetic acid. ¹H NMR (400 MHz, dmso)δ 8.66 (d, 1H), 8.51 (d, 1H), 7.62 (dd, 2H), 7.54-7.36 (m, 4H),7.36-7.02 (m, 3H), 6.92 (t, 1H), 6.53 (d, 2H), 5.17 (d, 1H), 3.26 (s,2H), 2.95 (d, 2H), 2.52-2.42 (m, 13H), 1.99 (s, 2H), 1.87 (s, 1H). MS(m/z) 570.8 [M+H]⁺.

Example 185

Synthesis of (S)-tert-butyl2-(3,5-difluorophenyl)-1-(5-(isoquinolin-5-yl)pyrimidin-4-yl)ethylcarbamate(185A)

The title compound as prepared according to the method presented in thesynthesis of 136B in Example 136 utilizing 172A andisoquinolin-6-ylboronic acid to provide the title compound. MS (m/z)463.3 [M+H]⁺.

Synthesis of(S)-2-(3,5-difluorophenyl)-1-(5-(isoquinolin-5-yl)pyrimidin-4-yl)ethanamine(185B)

The title compound as prepared according to the method presented in thesynthesis of 136C in Example 136 utilizing (S)-tert-butyl2-(3,5-difluorophenyl)-1-(5-(isoquinolin-5-yl)pyrimidin-4-yl)ethylcarbamateto provide the title compound.

Synthesis of2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(5-(isoquinolin-5-yl)pyrimidin-4-yl)ethyl)acetamide(185C)

The title compound as prepared (4 mg) according to the method presentedin the synthesis of Example 54 utilizing 60G and 185B. The titlecompound exists as a mixture of rotational isomers which was confirmedby a high temperature NMR experiment. ¹H NMR (400 MHz, dmso) δ 9.62 (s,1H), 9.56 (s, 1H), 9.44-9.38 (m, 1H), 9.05 (d, 1H), 8.88 (t, 1H),8.75-8.67 (m, 2H), 8.46-8.29 (m, 3H), 8.01-7.60 (m, 3H), 7.58 (d, 1H),7.36 (s, 1H), 7.10-6.92 (m, 3H), 6.92-6.68 (m, 2H), 6.44 (s, 2H), 6.21(d, 2H), 4.90 (d, 2H), 4.78-4.45 (m, 8H), 2.97 (t, 3H), 2.91-2.82 (m,1H), 2.50-2.41 (m), 1.34 (d, 2H), 0.88 (s, 1H), 0.81 (s, 1H). MS (m/z)609.4 [M+H]⁺.

Examples 186 and 187

Synthesis of5-(2-((S)-2-(3,5-difluorophenyl)-1-(2-((4aS,5aS)-3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamideand5-(2-((S)-2-(3,5-difluorophenyl)-1-(2-((4aR,5aR)-3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(186 and 187)

The title compounds were separated from the diastereomeric mixture 169Gby semi-preparative chiral HPLC fitted with a Chiralpak IC columnrunning a 70:30 mixture of Hep:IPA to obtain the desired compounds aspure diastereomers: 186 (4 mg): HPLC rt=12.4 min; MS (m/z) 600.4 [M+H]⁺.187 (3 mg): HPLC rt=14.0 min; MS (m/z) 600.4 [M+H]⁺. Absolutestereochemistry is unknown.

Example 188

Synthesis of(R)—N—((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)morpholine-3-carboxamide(188)

The title compound was prepared (6 mg) according to the method presentedin the synthesis of Example 125 utilizing 133.

Example 189

Synthesis of ethyl2-(3-(trifluoromethyl)-4,6-dihydro-2H-thieno[3,4-c]pyrazol-2-yl)acetate(189B) and 300 mg of ethyl2-(3-(trifluoromethyl)-4,6-dihydro-1H-thieno[3,4-c]pyrazol-1-yl)acetate(189C)

Compound 189B and 189C were prepared according to the method presentedfor the synthesis of Example 122 substituting dihydrothiophen-3(2H)-onefor 122B to provide 80 mg of 189B and 300 mg of 189C. 189B: MS (m/z) 281[M+H]⁺ and 189C: MS (m/z) 281 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,6-dihydro-1H-thieno[3,4-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(189D)

Compound 189D was prepared according to the method presented for thesynthesis of Example 122 substituting 189C for 122D to provide 18 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.76-8.68 (m, 1H), 7.72-7.63(m, 1H), 7.52-7.42 (m, 1H), 7.42-7.25 (m, 2H), 7.25-7.17 (m, 1H), 6.67(t, 1H), 6.32 (d, 2H), 5.35 (t, 1H), 4.91 (s, 2H), 3.94 (d, 4H), 3.05(d, 2H). MS (m/z) 606 [M+H]⁺.

Example 190

Synthesis of tert-butyl2-(2-ethoxy-2-oxoethyl)-3-(trifluoromethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate(190B), tert-butyl1-(2-ethoxy-2-oxoethyl)-3-(trifluoromethyl)-5,6-dihydropyrrolo[3,2-c]pyrazole-4(1H)-carboxylate(190C) and tert-butyl1-(2-ethoxy-2-oxoethyl)-3-(trifluoromethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate(190D)

Compound 190B, 190C and 190D were prepared according to the methodpresented for the synthesis of Example 122 substituting tert-butyl3-oxopyrrolidine-1-carboxylate for 122B to provide 60 mg of 190B, 35 mgof 190C and 60 mg of 190D. 190B: MS (m/z) 364 [M+H]⁺, 190C: MS (m/z) 364[M+H]⁺ and 190D: MS (m/z) 364 [M+H]⁺.

Synthesis of (S)-tert-butyl1-(2-((1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)amino)-2-oxoethyl)-3-(trifluoromethyl)-5,6-dihydropyrrolo[3,2-c]pyrazole-4(1H)-carboxylate(190E)

Compound 190E was prepared according to the method presented for thesynthesis of Example 122 substituting 190C for 122D to provide 46 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.70 (d, 1H), 7.61 (d, 1H),7.42 (d, 2H), 7.31 (s, 1H), 7.27-7.16 (m, 1H), 6.66 (t, 1H), 6.32 (d,2H), 5.34 (t, 1H), 4.96 (s, 2H), 4.46 (dd, 4H), 3.06 (dd, 3H), 1.50 (s,9H). MS (m/z) 689 [M+H]⁺.

Example 191

Synthesis of 3-(2-((IS)-2-(3,5-difluorophenyl)-1-(2-(2-oxoindolin-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(191)

Compound 191 was prepared according to the method presented for thesynthesis of Example 50 utilizing 50C and 2-(2-oxoindolin-3-yl)aceticacid to provide 44 mg of title compound: ¹H NMR (400 MHz, dmso) δ 9.83(d, 1H), 9.03-8.72 (m, 1H), 8.64 (d, 1H), 8.01-7.70 (m, 2H), 7.67-7.45(m, 2H), 7.44-7.25 (m, 2H), 7.02 (dt, 1H), 6.86 (t, 1H), 6.71 (ddd, 2H),6.47 (d, 2H), 5.19-4.96 (m, 1H), 3.82 (dt, 1H), 2.93 (dd, 2H), 2.40-2.16(m, 2H); MS (m/z) 527 [M+H]⁺.

Example 192

Synthesis of 3-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(2-oxoindolin-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(192)

Compound 192 was purified from compound 191 by RP HPLC using a C18column with a gradient of H₂O, 0.1% TFA-acetonitrile. The fast eluentwas collected and concentrated to provide 18 mg of title compound: ¹HNMR (400 MHz, dmso) δ 9.89 (s, 1H), 8.82 (d, 1H), 8.69-8.61 (m, 1H),8.02-7.81 (m, 2H), 7.70-7.56 (m, 2H), 7.48-7.27 (m, 4H), 7.06 (t, 2H),6.92 (t, 1H), 6.85-6.70 (m, 2H), 6.51 (d, 2H), 5.14 (d, 1H), 3.88 (t,2H), 2.99 (d, 2H), 2.44-2.20 (m, 2H). MS (m/z) 527 [M+H]⁺.

Example 193

Synthesis of5-(2-((1S)-2-(3,5)-difluorophenyl)-1-(5-methyl-2-oxoindolin-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(193)

Compound 193 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(5-methyl-2-oxoindolin-3-yl)acetic acid to provide 18 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.71 (s, 1H), 7.69 (dd, 1H), 7.49(ddd, 1H), 7.45-7.07 (m, 3H), 7.07-6.57 (m, 511), 6.27 (t, 2H), 5.34(dd, 1H), 3.71 (t, 1H), 3.04-2.85 (m, 3H), 2.75-2.62 (m, 1H). MS (m/z)559 [M+H]⁺.

Example 194

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5,5-dioxido-3-(trifluoromethyl)-4,6-dihydro-1H-thieno[3,4-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(194)

Compound 194 was prepared according to the method presented for thesynthesis of Example 197 utilizing 189 (60 mg, 0.1 mmol),3-Chloroperbenzoic acid (87 mg, 77% max., 0.2 mmol) in DCM (3 mL) at 0°C. to provide 20 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.61(dd, 1H), 7.93-7.80 (m, 1H), 7.61 (s, 1H), 7.58-7.44 (m, 2H), 7.44-7.30(m, 2H), 7.19 (ddd, 3H), 6.56 (tt, 1H), 6.23 (dd, 2H), 5.38 (s, 1H),5.25 (dd, 1H), 4.91 (d, 2H), 4.75 (s, 5H), 4.45-4.18 (m, 4H), 4.00 (dd,1H), 3.21 (dt, 3H), 3.09-2.86 (m, 2H), 2.22-2.03 (m, 1H), 1.91 (s, 1H),1.17 (dd, 2H), 1.13-0.97 (m, 1H), 0.80 (dd, 1H). MS (m/z) 638 [M+H]⁺

Example 195

Synthesis of2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(4-(methoxymethyl)phenyl)pyridin-2-yl)ethyl)acetamide(195)

Compound 195 was prepared according to the method presented for thesynthesis of Example 68 utilizing 68A and(4-(methoxymethyl)phenyl)boronic acid to provide 13 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.65 (d, 1H), 7.63 (dd, 8.0 Hz, 2H),7.45 (dd, 2H), 7.35 (dd, 3H), 7.14-7.01 (m, 2H), 6.68 (ddd, 3H), 6.24(d, 2H), 5.44 (dd, 1H), 4.48 (d, 2H), 3.38 (s, 3H), 2.97 (dd, 2H),2.56-2.34 (m, 2H), 1.37 (s, 1H), 1.04 (d, 1H). MS (m/z) 601 [M+H]⁺.

Example 196

Synthesis of 3-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5-fluoro-2-oxoindolin-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(196)

Compound 196 was prepared according to the method presented for thesynthesis of Example 50 utilizing 50C and2-(5-fluoro-2-oxoindolin-3-yl)acetic acid to provide 27 mg of titlecompound: ¹H NMR (400 MHz, dmso) δ 9.89 (d, 1H), 8.89 (dd, 1H), 8.66(dd, 1H), 8.07-7.72 (m, 2H), 7.72-7.50 (m, 2H), 7.50-7.23 (m, 3H),7.13-6.59 (m, 4H), 6.47 (d, 2H), 5.22-5.02 (m, 1H), 3.92-3.79 (m, 1H),2.95 (dd, 2H), 2.34 (ddd, 1H). MS (m/z) 545 [M+H]⁺.

Example 197

Synthesis of(S)-3-(3-carbamoyl-4-fluorophenyl)-2-(2-(3,5-difluorophenyl)-1-(2-(5,5-dioxido-3-(trifluoromethyl)-6,7-dihydrothiopyrano[4,3-c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridine-1-oxide(197) and(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5,5-dioxido-3-(trifluoromethyl)-6,7-dihydrothiopyrano[4,3-c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(263)

232 (120 mg, 0.194 mmol) and 3-Chloroperbenzoic acid (87 mg, 77% max.,0.2 mmol) in DCM (5 mL) at 0° C., was stirred for 2 hours. Solvents wereconcentrated in vacuo and the residue was purified by RP HPLC using aC18 column with a gradient of H₂O, 0.1% TFA-acetonitrile, to provide 25mg of 197 and 27 mg of 263: 1H NMR (400 MHz, cd3od) δ 8.94 (d, 1H), 8.33(d, 1H), 7.92-7.79 (m, 1H), 7.51-7.30 (m, 3H), 7.19-7.09 (m, 1H), 6.65(t, 1H), 6.34 (d, 2H), 5.46-5.29 (m, 1H), 4.85 (d, 2H), 4.19 (s, 2H),3.18-2.94 (m, 4H), 0.02-3.24 (m, 6H), 3.57-3.44 (m, 1H), 3.31 (d, 2H);MS (m/z) 668 [M+H]⁺.

Example 198

Synthesis of 5-(2-((IS)-1-(2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(198)

Compound 198 was prepared according to the method presented for thesynthesis of Example 122 substituting ethyl 2,2-difluoroacetate forethyl 2,2,2-trifluoroacetate to provide 48 mg of title compound: ¹H NMR(400 MHz, cd₃od) δ 8.48 (d, 1H), 7.45 (d, 1H), 7.33-7.17 (m, 2H), 7.12(s, 1H), 7.08-6.95 (m, 1H), 6.57-6.22 (m, 2H), 6.12 (d, 2H), 5.14 (t,1H), 4.57-4.38 (m, 2H), 2.93-2.77 (m, 2H), 2.58 (dd, 1H), 2.44 (dd, 1H),1.89 (d, 2H), 0.86 (d, 1H), 0.01 (dd, 1H). MS (m/z) 582 [M+H]⁺.

Example 199

Synthesis of 6,6-difluorobicyclo[3.1.0]hexan-3-one (199A)

Compound 199A was prepared according to the method presented in the page153 of WO 2011/059887 to provide 2.77 g of crude title compound. MS(m/z) 133 [M+H]⁺.

Synthesis of ethyl2-(4,4-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(199C) and ethyl 2-(5-fluoro-3-(trifluoromethyl)-1H-indazol-1-yl)acetate(199D)

Compound 199C and 199D were prepared according to the method presentedfor the synthesis of Example 122 substituting 199A for 122B to provide0.4 g of 199C and 2 g of 199D. 199C: MS (m/z) 311 [M+H]⁺ and 199D: MS(m/z) 291 [M+H]⁺.

Synthesis of5-(2-((1S)-1-(2-(4,4-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(199E)

Compound 199E was prepared according to the method presented for thesynthesis of Example 122 substituting 199C for 122D to provide 23 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.70 (d, 1H), 7.65 (dd, 1H),7.45 (dt, 2H), 7.30 (s, 1H), 7.27-7.15 (m, 1H), 6.66 (dd, 1H), 6.32 (t,2H), 5.34 (t, 1H), 4.82-4.70 (m, 2H), 3.15-2.93 (m, 5H), 2.85 (dd, 1H).MS (m/z) 636 [M+H]⁺.

Example 200

Synthesis of (S)-tert-butyl2-(2-((1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)amino)-2-oxoethyl)-3-(trifluoromethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate(200A)

Compound 200A was prepared according to the method presented for thesynthesis of Example 122 substituting 60 mg 190B for 122D to provide 35mg of title compound: MS (m/z) 689 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(200B)

200A (35 mg, 0.05 mmol) and trifluoroacetic acid (1 mL) was stirred for1 hours. Solvents were concentrated in vacuo and the residue waspurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, to provide 5 mg of title product: ¹H NMR (400 MHz,cd₃od) δ 8.76-8.65 (m, 1H), 7.59 (dd, 1H), 7.49-7.35 (m, 2H), 7.29 (s,1H), 7.20 (dd, 1H), 6.67 (t, 1H), 6.35 (d, 2H), 5.34 (t, 1H), 5.00 (s,2H), 4.51 (s, 2H), 4.43 (s, 2H), 3.06 (ddd, 2H); MS (m/z) 589 [M+H]⁺

Example 201

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(2-oxo-1,2-dihydroquinolin-4-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(201)

Compound 201 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(2-oxo-1,2-dihydroquinolin-4-yl)acetic acid to provide 83 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.61 (dd, 1H), 7.57 (d, 1H),7.50-7.37 (m, 2H), 7.37-7.18 (m, 4H), 7.16-7.01 (m, 2H), 6.65-6.48 (m,1H), 6.45 (s, 1H), 6.25 (d, 2H), 5.26 (t, 1H), 3.75 (s, 2H), 3.07-2.86(m, 2H); MS (m/z) 557 [M+H]⁺.

Example 202

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5-methoxy-2-oxoindolin-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(202)

Compound 202 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(5-methoxy-2-oxoindolin-3-yl)acetic acid to provide 17 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.61 (dd, 1H), 7.53 (dd, 1H),7.43-7.34 (m, 1H), 7.29 (dd, 1H), 7.25-6.96 (m, 2H), 6.77-6.41 (m, 4H),6.21 (dd, 2H), 5.37-5.15 (m, 1H), 3.79 (dt, 1H), 3.61 (d, 3H), 3.10-2.81(m, 2H), 2.69-2.48 (m, 2H). MS (m/z) 575 [M+H]⁺.

Example 203

Synthesis of ethyl2-(3-(trifluoromethyl)-4,6-dihydro-2H-furo[3,4-c]pyrazol-2-yl)acetate(203B) and ethyl2-(3-(trifluoromethyl)-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)acetate(20° C.)

Compound 203B and 203C were prepared according to the method presentedfor the synthesis of Example 122 substituting dihydrofuran-3(2H)-one for122B to provide 82 mg of 203B and 500 mg of 203C: 203B: MS (m/z) 265[M+H]⁺ and 203C: MS (m/z) 265 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,6-dihydro-2H-furo[3,4-c]pyrazol-2-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(203D)

Compound 203D was prepared according to the method presented for thesynthesis of Example 122 substituting 203B for 122D to provide 33 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.75-8.67 (m, 1H), 7.63 (dd,1H), 7.49-7.37 (m, 2H), 7.32 (s, 1H), 7.26-7.16 (m, 1H), 6.66 (t, 1H),6.32 (d, 2H), 5.35 (t, 11-H), 4.92 (d, 4H), 4.79 (s, 2H), 3.05 (dd, 2H).MS (m/z) 590 [M+H]⁺.

Example 204

Synthesis of(S)-5-(2-(1-(2-(5,5-dioxido-3-(trifluoromethyl)-6,7-dihydrothiopyrano[4,3-c]pyrazol-1(4H)-yl)acetamido)-2-(3-fluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(204)

Compound 204 was prepared according to the method presented for thesynthesis of Example 197 utilizing 228 (62 mg, 0.1 mmol),3-Chloroperbenzoic acid (87 mg, 77% max., 0.2 mmol) in DCM (3 mL) at 0°C. to provide 39 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.68(dd, 1H), 7.51 (dd, 1H), 7.42-7.31 (m, 2H), 7.15 (t, 2H), 7.05 (td, 1H),6.81 (td, 1H), 6.52 (d, 1H), 6.43 (d, 1H), 5.40-5.28 (m, 1H), 4.87 (d,2H), 4.32-4.17 (m, 2H), 3.44-3.24 (m, 4H), 3.24-2.95 (m, 4H). MS (m/z)634 [M+H]⁺

Example 205

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5,7-dimethyl-2-oxoindolin-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(205)

Compound 205 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(5,7-dimethylindolin-3-yl)acetic acid to provide 19 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.68 (t, 1H), 7.61 (dd, 1H),7.54-7.34 (m, 2H), 7.34-7.09 (m, 2H), 6.97-6.54 (m, 3H), 6.30 (dd, 2H),5.37-5.24 (m, 1H), 3.83 (dd, 1H), 3.15-2.89 (m, 3H), 2.76-2.54 (m, 2H),2.17 (dd, 6H). MS (m/z) 573 [M+H]⁺.

Example 206

Synthesis ofN—((S)-1-(3-(4-(cyclopropylmethoxy)phenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(206)

Compound 206 was prepared according to the method presented for thesynthesis of Example 68 utilizing 68A and(4-(cyclopropylmethoxy)phenyl)boronic acid to provide 5 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.26 (s, 1H), 7.24 (d, 1H),7.11-7.00 (m, 1H), 6.68-6.18 (m, 6H), 5.91 (s, 2H), 5.13 (s, 1H), 3.49(d, 2H), 2.63 (s, 2H), 2.12 (s, 2H), 1.03 (s, 3H), 0.80-0.63 (m, 2H),0.27 (d, 2H), 0.01 (d, 2H). MS (m/z) 627 [M+H]⁺.

Example 207

Synthesis of 2-(5-isobutyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)aceticacid (207B)

Compound 207B was prepared according to the method presented for thesynthesis of Example 238 substituting1,1,1-trifluoro-6-methylheptane-2,4-dione for 238A to provide 650 mg oftitle compound. MS (m/z) 251 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-isobutyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(207C)

Compound 207 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(5-isobutyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid to provide20 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.69 (dd, 1H), 7.63(dd, 1H), 7.48-7.38 (m, 2H), 7.32 (s, 1H), 7.21 (dd, 1H), 6.67 (dd, 1H),6.39 (s, 1H), 6.32 (d, 2H), 5.36 (t, 1H), 4.88 (s, 2H), 3.05 (d, 2H),2.42 (dd, 2H), 1.84 (dt, 1H), 0.88 (dd, 6H). MS (m/z) 604 [M+H]⁺.

Example 208

Synthesis of ethyl2-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (208A)

Compound 208A was prepared according to the method presented for thesynthesis of Example 74 substituting5-bromo-3-(trifluoromethyl)-1H-pyrazole for 74B to provide 300 mg oftitle compound. MS (m/z) 300 [M+H]⁺.

Synthesis of ethyl2-(5-(methoxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (208B)

To a solution of 208A (300 mg, 0.1 mmol) and potassiumtrifluoro(methoxymethyl)borate (304 mg, 0.2 mmol) in 3 ml dioxane/water(10:1) was added 3 aq. Cs₂CO₃ and2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (Ruphos) (93.4 mg,0.2 mmol) and Palladium(II)acetate (22.5 mg, 0.1 mmol). The resultingmixture was heated at reflux for overnight. The reaction mixture wasfiltered and the mixture was extracted with EtOAc. The organics weredried over Na₂SO₄, filtered and concentrated. The crude product waspurified by SiO₂ chromatography eluting with a gradient of EtOAc inhexanes to provide 12 mg of title compound. MS (m/z) 267 [M+H]⁺.

Synthesis of2-(5-(methoxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid(208C)

Compound 208C was prepared according to the method presented for thesynthesis of Example 74 substituting 208B for 74B to provide 10 mg oftitle compound. MS (m/z) 239 [M+H]⁺.

Synthesis of(S)-2-fluoro-5-(2-(2-(3-fluorophenyl)-1-(2-(5-(methoxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(208D)

Compound 208D was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and 208D to provide 3 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.68 (dd, 1H), 7.59 (dd, 1H), 7.40(dd, 2H), 7.29 (s, 1H), 7.21 (dd, 1H), 6.73-6.62 (m, 1H), 6.59 (s, 1H),6.31 (d, 2H), 5.35 (t, 1H), 4.95 (s, 2H), 4.47-4.36 (m, 2H), 3.23 (s,3H), 3.07-3.01 (m, 2H). MS (m/z) 592 [M+H]⁺.

Example 209

Synthesis of1-(2-(((S)-1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)amino)-2-oxoethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxamide(209)

H₂O₂ (30 wt %, excess) was added to a suspension of 242 (30 mg, 0.054mmol) and potassium carbonate (74.5 mg, 0.54 mmol) in DMSO (1 mL) at 0°C. and then stirred for 1 hour. The suspension was filtered and thefiltrate was purified by RP HPLC using a C18 column with a gradient ofH₂O, 0.1% TFA-acetonitrile, to provide 18 mg of the title compound; ¹HNMR (400 MHz, cd₃od) δ 8.51 (dd, 1H), 7.51 (d, 1H), 7.37-7.24 (m, 2H),7.15 (s, 1H), 7.11-6.99 (m, 1H), 6.49 (t, 1H), 6.13 (d, 2H), 5.22-5.08(m, 1H), 4.59-4.43 (m, 2H), 2.85 (dd, 2H), 2.66-2.53 (m, 1H), 2.50-2.39(m, 1H), 2.04 (s, 1H), 1.87 (s, 1H), 0.88 (dd, 1H), 0.01 (dt, 1H). MS(m/z) 575 [M+H]⁺

Example 210

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-methyl-3-(trifluoromethyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(210)

A mixture of 200B (30 mg, 0.05 mmol) and formaldehyde (15.3 mg, 0.5mmol) in acetic acid (1 mL) was stirred for 30 minutes. Sodiumcyanoborohydride (4.8 mg, 0.076 mmol) was added to the suspension andstirred for 1 hour. Solvents were concentrated in vacuo and the residuewas purified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, to provide 18 mg of the title compound: ¹H NMR (400MHz, cd₃od) δ 8.71 (dd, 1H), 7.59 (dd, 1H), 7.50-7.37 (m, 2H), 7.29 (s,1H), 7.20 (dd, 1H), 6.67 (t, 1H), 6.35 (d, 2H), 5.34 (t, 1H), 5.01 (s,2H), 4.64 (s, 4H), 3.16 (s, 3H), 3.07 (ddd, 2H); MS (m/z) 603 [M+H]⁺

Example 211

Synthesis of 2-(3-cyano-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)aceticacid (211B)

Compound 211B was prepared according to the method presented for thesynthesis of Example 74 substituting1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile (211A) for1-7,8,8-trimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-4,7-methanoindazole(74A) to provide 300 mg of title compound: MS (m/z) 192 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(3-cyano-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(211C)

Compound 211C was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(3-cyano-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetic acid (211B)to provide 42 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.71 (dd,1H), 7.67 (dd, 1H), 7.47 (dd, 2H), 7.33 (s, 1H), 7.23 (dd, 1H), 6.67 (t,1H), 6.33 (d, 2H), 5.35 (t, 1H), 4.81 (s, 2H), 3.06 (d, 2H), 2.77-2.48(m, 6H). MS (m/z) 545 [M+H]⁺.

Example 212

Synthesis of 5-(2-((1S)-1-(2-(3-(difluoromethyl)-5-hydroxy-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(212)

Compound 212 was prepared according to the method presented for thesynthesis of Example 154 substituting 233B for 154B to provide 12 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.61 (dd, 1H), 7.57 (d, 1H),7.37 (dd, 2H), 7.28-7.08 (m, 2H), 6.78-6.34 (m, 2H), 6.32-6.14 (m, 2H),5.39-5.17 (m, 2H), 4.66 (ddd, 2H), 3.04-2.88 (m, 2H), 2.19-1.99 (m, 2H),0.95-0.65 (m, 2H). MS (m/z) 598 [M+H]⁺.

Example 213

Synthesis of 2-(3-(trifluoromethyl)-1H-indazol-1-yl)acetic acid (213B)

Compound 213B was prepared according to the method presented for thesynthesis of Example 74 substituting 3-(trifluoromethyl)-1H-indazole(213A) for1-7,8,8-trimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-4,7-methanoindazole(74A) to provide 155 mg of title compound. MS (m/z) 245 [M+H]⁺.

Synthesisof(S)-2-fluoro-5-(2-(2-(3-fluorophenyl)-1-(2-(3-(trifluoromethyl)-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(213B)

Compound 213 was prepared according to the method presented for thesynthesis of Example 59 utilizing 59D and2-(3-(trifluoromethyl)-1H-indazol-1-yl)acetic acid (213B) to provide 25mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd, 1H), 7.78 (d,1H), 7.63 (dd, 1H), 7.59-7.41 (m, 3H), 7.38-7.11 (m, 4H), 7.04 (dd, 1H),6.82 (t, 1H), 6.47 (dd, 2H), 5.34 (t, 1H), 5.23 (s, 2H), 3.07 (d, 2H).MS (m/z) 580 [M+H]⁺.

Example 214

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(naphthalen-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(214)

Compound 214 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and 2-(naphthalen-1-yl)acetic acidto provide: ¹H NMR (400 MHz, cdcl₃) δ 8.76 (d, 1H), 8.69 (d, 1H), 7.94(d, 1H), 7.80 (dd, 3H), 7.72-7.66 (m, 1H), 7.61 (d, 1H), 7.49-7.34 (m,3H), 7.34-7.25 (m, 1H), 6.99 (d, 1H), 6.10 (d, 2H), 5.39 (dd, 1H), 4.01(p, 2H), 2.99 (ddd, 2H). MS (m/z) 540 [M+H]⁺.

Example 215

Synthesis of5-(2-((1S)-1-(2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(215)

215 was separated from the diastereomeric mixture of 60 bysemi-preparative chiral HPLC fitted with a Chiralcel AZ-H column runninga 70:30 mixture of Hep:IPA. The fast eluent was collected to obtain 58mg of the single diastereomer: ¹H NMR (400 MHz, cd₃od) δ 8.65 (dd, 1H),7.53 (dd, 1H), 7.35 (dd, 2H), 7.33-7.12 (m, 2H), 6.87-6.48 (m, 2H), 6.26(d, 2H), 5.40-5.28 (m, 1H), 4.79 (s, 2H), 3.00 (qd, 2H), 2.51-2.36 (m,2H), 1.16-1.08 (m, 1H), 1.02 (d, 1H). MS (m/z) 618 [M+H]⁺.

Example 216

Synthesis of5-(2-((1S)-1-(2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(216)

216 was separated from the diastereomeric mixture of 60 bysemi-preparative chiral HPLC fitted with a Chiralcel AZ-H column runninga 70:30 mixture of Hep:IPA. The slow eluent was collected to obtain 58mg of the single diastereomer: ¹H NMR (400 MHz, cd₃od) δ 8.66 (dd, 1H),7.52 (dd, 1H), 7.35 (dd, 2H), 7.31-7.13 (m, 2H), 6.83-6.48 (m, 2H), 6.26(d, 2H), 5.40-5.26 (m, 1H), 4.79 (s, 2H), 3.12-2.93 (m, 2H), 2.44 (ddd,2H), 1.18-1.10 (m, 1H), 1.10-1.00 (m, 1H). MS (m/z) 618 [M+H]⁺.

Example 217

Synthesis of2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(4-(2-methoxyethoxy)phenyl)pyridin-2-yl)ethyl)acetamide(217)

Compound 217 was prepared according to the method presented for thesynthesis of Example 68 utilizing 68A and(4-(2-methoxyethoxy)phenyl)boronic acid to provide 8 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.61 (d, 1H), 7.61 (d, 1H), 7.41(dd, 1H), 7.07-6.87 (m, 4H), 6.68 (ddd, 2H), 6.25 (d, 2H), 5.48 (d, 1H),4.13 (d, 2H), 3.81-3.70 (m, 2H), 3.42 (s, 3H), 2.96 (dd, 2H), 2.46 (s,2H), 1.37 (s, 1H), 1.07 (s, 1H). MS (m/z) 631 [M+H]⁺.

Example 218

Synthesis of(S)-3-(3-carbamoyl-4-fluorophenyl)-2-(2-(3,5-difluorophenyl)-1-(2-(5,5-dioxido-3-(trifluoromethyl)-4,6-dihydro-1H-thieno[3,4-c]pyrazol-1-yl)acetamido)ethyl)pyridine1-oxide (218)

Compound 218 was prepared according to the method presented for thesynthesis of Example 197 utilizing 189 to provide 25 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.32 (d, 1H), 7.85 (dd, 1H),7.54-7.44 (m, 1H), 7.44-7.28 (m, 2H), 7.21 (d, 1H), 7.18-7.07 (m, 1H),6.62 (t, 1H), 6.33 (d, 2H), 5.48-5.31 (m, 1H), 5.03-4.85 (m, 2H),4.42-4.17 (m, 3H), 3.51 (dd, 1H), 3.04 (dd, 1H). MS ((m/z) 654 [M+H]⁺

Example 219

Synthesisof(S)-5-(2-(1-(2-(5-acetyl-3-(trifluoromethyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(219)

Compound 219 was prepared according to the method presented for thesynthesis of Example 54 substituting 251 for 54B to provide 32 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.75-8.67 (m, 1H), 7.64 (d,1H), 7.58-7.40 (m, 2H), 7.25 (dd, 2H), 6.66 (t, 1H), 6.32 (d, 2H), 5.35(dd, 1H), 4.92 (d, 2H), 4.69 (d, 2H), 4.51 (d, 2H), 3.16-3.01 (m, 2H),2.11 (d, 3H). MS (m/z) 631 [M+H]⁺.

Example 220

Synthesis of2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-2-yl)aceticacid (220A)

Compound 220A was prepared according to the method presented for thesynthesis of Example 181 substituting 60B for 122D to provide 8 mg oftitle compound. MS (m/z) 271 [M+H]⁺.

Synthesis of5-(2-((1S)-1-(2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-2-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(220B)

Compound 220B was prepared according to the method presented for thesynthesis of Example 154 substituting 220A for 181A to provide 6 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.62 (dd, 1H), 7.54 (dd, 1H),7.35 (dd, 2H), 7.15 (dd, 2H), 6.90 (td, 1H), 6.58 (t, 1H), 6.22 (d, 2H),5.26 (t, 1H), 4.94 (s, 2H), 3.05-2.89 (m, 2H), 2.78-2.67 (m, 1H),2.50-2.38 (m, 1H), 1.58 (dd, 1H), 1.40 (dd, 1H). MS (m/z) 596 [M+H]⁺.

Example 221

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(6,7-dimethyl-2-oxoindolin-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(221)

Compound 221 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(6,7-dimethylindolin-3-yl)acetic acid to provide 15 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.64 (td, 1H), 7.71-7.56 (m, 1H),7.49-7.40 (m, 1H), 7.40-6.91 (m, 3H), 6.76 (dd, 1H), 6.66-6.49 (m, 2H),6.49-6.10 (m, 3H), 5.22 (dd, 1H), 3.61 (dd, 1H), 2.99-2.47 (m, 5H),2.22-1.94 (m, 6H). MS (m/z) 573 [M+H]⁺.

Example 222

Synthesis of 2-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid(222A)

Compound 222A was prepared according to the method presented for thesynthesis of Example 74 substituting5-bromo-3-(trifluoromethyl)-1H-pyrazole for 74B to provide 270 mg oftitle compound. MS (m/z) 273 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3-fluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(222B)

Compound 222B was prepared according to the method presented for thesynthesis of Example 59 utilizing 59D and2-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (222A) toprovide 490 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.62 (dd,1H), 7.54 (dd, 1H), 7.35 (dd, 2H), 7.15 (dd, 2H), 6.90 (td, 1H), 6.58(t, 1H), 6.22 (d, 2H), 5.26 (t, 1H), 4.94 (s, 2H), 3.05-2.89 (m, 2H),2.78-2.67 (m, 1H), 2.50-2.38 (m, 1H), 1.58 (dd, 1H), 1.40 (dd, 1H). MS(m/z) 608 [M+H]⁺.

Example 223

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5,7-dimethyl-2-oxoindolin-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(223)

Compound 223 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(5,7-dimethylindolin-3-yl)acetic acid to provide 19 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.70-8.54 (m, 1H), 7.76-7.52 (m,1H), 7.33 (dddd, 41), 6.79-6.46 (m, 3H), 6.27 (dd, 2H), 5.39-5.21 (m,1H), 4.04 (dd, 2H), 3.07-2.56 (m, 5H), 2.31-2.09 (m, 6H). MS (m/z) 573[M+H]⁺.

Example 224

Synthesis of2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(4-isopropoxyphenyl)pyridin-2-yl)ethyl)acetamide(224)

Compound 224 was prepared according to the method presented for thesynthesis of Example 68 utilizing 68A and (4-isopropoxyphenyl)boronicacid to provide 14 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.61(d, 1H), 7.64 (d, 1H), 7.43 (dd, 1H), 7.04-6.95 (m, 2H), 6.89 (dd, 2H),6.68 (ddd, 2H), 6.26 (s, 2H), 5.50 (d, 1H), 4.69-4.56 (m, 1H), 2.96 (t,2H), 2.46 (s, 2H₁), 1.46-1.21 (m, 7H), 1.02 (s, 1H). MS (m/z) 615[M+H]⁺.

Example 225

Synthesis ofN—((S)-1-(3-(3-carbamoylphenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxamide(225)

Compound 225 was prepared according to the method presented for thesynthesis of Example 50 utilizing 50C and2′-oxospiro[cyclopropane-1,3′-indoline]-2-carboxylic acid to provide 46mg of title compound: ¹H NMR (400 MHz, dmso) δ 10.56 (d, 1H), 8.91 (dd,1H), 8.50 (dd, 1H), 8.06-7.85 (m, 2H), 7.78-7.21 (m, 6H), 7.12-6.56 (m,5H), 6.50 (d, 1H), 6.18 (d, 1H), 5.17 (dd, 1H), 2.94 (d, 1H), 2.86-2.71(m, 1H), 2.63 (t, 1H), 1.88-1.76 (m, 1H), 1.61-1.50 (m, 1H). MS (m/z)539 [M+H]⁺.

Example 226

Synthesis of 7H-pyrrolo[2,3-d]pyrimidin-2-amine (226A)

A solution of 266A in 10 mL of NH₃ (7N in MeOH) was heated at 130° C. insealed tube overnight. The reaction was monitored by LC/Mass untilcompletion. Remove the solvent and used as crude. MS (m/z) 135 [M+H]⁺.

Synthesis of 2 ethyl 2-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate(226B)

Compound 266B was prepared according to the method presented for thesynthesis of Example 74 substituting 7H-pyrrolo[2,3-d]pyrimidin-2-amine(226A) for 17,8,8-trimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-4,7-methanoindazole(74A) to provide 20 mg of title compound. MS (m/z) 221 [M+H]⁺.

Synthesis of(S)-3-(2-(1-(2-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(226C)

Compound 226C was prepared according to the method presented for thesynthesis of Example 50 utilizing 50C and2-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic (226B) to provide 15mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.64-8.54 (m, 1H), 8.40(s, 1H), 7.77 (d, 1H), 7.56-7.45 (m, 2H), 7.37 (t, 1H), 7.30 (dd, 1H),7.15 (d, 1H), 7.06 (d, 1H), 6.55 (t, 1H), 6.43 (d, 1H), 6.15 (d, 2H),5.44-5.31 (m, 3H), 2.93 (ddd, 2H). MS (m/z) 528 [M+H]⁺.

Example 227

Synthesis of(S)-tert-butyl1-(2-((1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)amino)-2-oxoethyl)-3-(trifluoromethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate(227)

Compound 227 was prepared according to the method presented for thesynthesis of Example 122 substituting 190D for 122D to provide 40 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.70 (s, 1H), 7.65 (d, 1H),7.51-7.18 (m, 4H), 6.65 (s, 1H), 6.32 (s, 2H), 5.35 (d, 1H), 4.89 (d,2H), 4.43 (d, 4H), 3.06 (d, 2H), 1.49 (d, 9H). MS (m/z) 689 [M+H]⁺.

Example 228

Synthesis of2-(3-(trifluoromethyl)-6,7-dihydrothiopyrano[4,3-c]pyrazol-1(4H)-yl)acetic acid (228A)

Compound 228A was prepared according to the method presented for thesynthesis of Example 122 substituting dihydro-2H-thiopyran-4(3H)-one for122B to provide 1 g of title compound. MS (m/z) 267 [M+H]⁺.

Synthesis of(S)-2-fluoro-5-(2-(2-(3-fluorophenyl)-1-(2-(3-(trifluoromethyl)-6,7-dihydrothiopyrano[4,3-c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)benzamide(228B)

Compound 228B was prepared according to the method presented for thesynthesis of Example 59 utilizing 59D and 228A to provide 27 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.72 (dd, 1H), 7.70 (dd, 1H), 7.50(dd, 1H), 7.38 (d, 1H), 7.28 (s, 1H), 7.20 (dd, 1H), 7.07 (dd, 1H), 6.84(td, 1H), 6.50 (dd, 2H), 5.33 (dd, 1H), 3.65 (d, 2H), 3.12-3.01 (m, 2H),2.87 (dd, 2H), 2.77-2.66 (m, 2H). MS (m/z) 602 [M+H]⁺.

Example 229

Synthesis of(S)-2-fluoro-5-(2-(2-(3-fluorophenyl)-1-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(229)

Compound 229 was prepared according to the method presented for thesynthesis of Example 59 utilizing 59D and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid toprovide 37 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd,1H), 7.66 (dd, 1H), 7.47 (dd, 1H), 7.36 (d, 1H), 7.25 (d, 1H), 7.20-7.14(m, 1H), 7.07 (dd, 1H), 6.83 (dd, 1H), 6.49 (dd, 2H), 5.35 (t, 1H), 4.78(s, 2H), 3.05 (d, 2H), 2.54 (t, 2H), 2.44 (s, 2H), 1.75 (dd, 4H). MS(m/z) 584 [M+H]⁺.

Example 230

Synthesis of2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)ethyl)acetamide(230)

Compound 230 was prepared according to the method presented for thesynthesis of Example 68 utilizing 68A and(4-(trifluoromethoxy)phenyl)boronic acid to provide 13 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.67 (d, 1H), 7.58 (d, 1H), 7.40(dd, 1H), 7.24 (s, 2H), 7.18-7.08 (m, 2H), 6.68 (ddd, 2H), 6.23 (d, 2H),5.38 (d, 1H), 2.99 (t, 2H), 2.46 (s, 2H), 1.37 (s, 1H), 1.03 (s, 1H). MS(m/z) 641 [M+H]⁺.

Example 231

Synthesis ofN—((S)-1-(3-(4-(difluoromethoxy)phenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(231)

Compound 231 was prepared according to the method presented for thesynthesis of Example 68 utilizing 68A and(4-(difluoromethoxy)phenyl)boronic acid to provide 4 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.65 (d, 1H), 7.58 (d, 1H), 7.39(dd, 1H), 7.09 (dd, 4H), 7.04-6.50 (m, 4H), 6.27 (s, 2H), 5.40 (s, 1H),2.99 (d, 2H), 2.46 (s, 2H), 1.37 (s, 1H), 1.10-1.02 (m, 1H). MS (m/z)641 [M+H]⁺.

Example 232

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-6,7-dihydrothiopyrano[4,3-c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(232)

Compound 232 was prepared according to the method presented for thesynthesis of Example 122 substituting dihydro-2H-thiopyran-4(3H)-one for122B to provide 130 mg of title compound: ¹H NMR (400 MHz, cdcl₃) δ 8.53(dd, 1H), 7.69-7.55 (m, 2H), 7.45 (dd, 1H), 7.30-7.07 (m, 3H), 6.88 (d,1H), 6.72 (d, 1H), 6.51 (ddd, 1H), 6.13 (d, 2H), 5.41 (dd, 1H), 3.68 (d,2H), 2.93-2.64 (m, 6H). MS (m/z) 620 [M+H]⁺.

Example 233

Synthesis of ethyl2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate

Compound 233A was prepared according to the method presented for thesynthesis of Example 181 substituting 60A for 122D to provide 450 mg oftitle compound. MS (m/z) 271 [M+H]⁺.

Synthesis of 5-(2-((1S)-1-(2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(233B)

Compound 233B was prepared according to the method presented for thesynthesis of Example 154 substituting 233A for 181A to provide 38 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd, 1H), 7.79-7.68 (m,1H), 7.57-7.48 (m, 1H), 7.42-7.24 (m, 2H), 7.16 (dd, 1H), 6.81-6.52 (m,2H), 6.25 (d, 2H), 5.30 (dd, 1H), 3.12-2.93 (m, 2H), 2.76-2.63 (m, 1H),2.46 (dt, 1H), 1.65-1.48 (m, 2H). MS (m/z) 596 [M+H]⁺.

Example 234

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5-methyl-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(234)

Compound 234 was prepared according to the method presented for thesynthesis of Example 122 substituting 3-methylcyclopentanone for 122B toprovide 42 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.70 (d, 1H),7.68 (dd, 1H), 7.47 (dd, 2H), 7.35 (s, 1H), 7.29-7.16 (m, 1H), 6.75-6.61(m, 1H), 6.33 (d, 2H), 5.44-5.30 (m, 1H), 4.77 (s, 2H), 3.07 (t, 3H),2.84 (dddd, 2H), 2.34-2.19 (m, 2H), 1.25-1.12 (m, 3H). MS (m/z) 602[M+H]⁺.

Example 235

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-methyl-3-(trifluoromethyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(235)

Compound 235 was prepared according to the method presented for thesynthesis of Example 210 substituting 251 for 200B to provide 22 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.71 (dd, 1H), 7.62 (ddd, 1.6Hz, 1H), 7.53 (d, 1H), 7.43 (ddd, 1H), 7.23 (dd, 2H), 6.67 (dd, 1H),6.33 (t, 2H), 5.38-5.27 (m, 1H), 4.95 (d, 2H), 4.53-4.39 (m, 2H),4.30-4.14 (m, 2H), 3.16-3.04 (m, 2H), 3.01 (d, 3H). MS (m/z) 603 [M+H]⁺.

Example 236

Synthesis of 2-(5-isopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)aceticacid (236B) and2-(3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (236C)

Compound 236B and 236C were prepared according to the method presentedfor the synthesis of Example 238 substituting1,1,1-trifluoro-5-methylhexane-2,4-dione for1,1,1-trifluoro-5,5-dimethylhexane-2,4-dione (238A) to provide 420 mg of236B and 400 mg of 236C. 236B: MS (m/z) 237 [M+H]⁺. 236C: MS (m/z) 237[M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(236D)

Compound 236D was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(3-isopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (236C) toprovide 22 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd,1H), 7.67 (dd, 1H), 7.55-7.40 (m, 2H), 7.33 (s, 1H), 7.22 (dd, 1H),6.75-6.61 (m, 1H), 6.49-6.27 (m, 3H), 5.36 (t, 1H), 4.90 (s, 2H), 3.06(d, 2H), 2.83 (dt, 1H), 1.24-1.09 (m, 6H). MS (m/z) 590 [M+H]⁺.

Example 237

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide (237)

Compound 237 was prepared according to the method presented for thesynthesis of Example 122 substituting 3-ethoxycyclopent-2-enone for 122Bto provide 3 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.65 (dt,1H), 7.54 (dd, 1H), 7.46 (dd, 1H), 7.42-7.26 (m, 2H), 7.19 (dd, 1H),6.63 (t, 1H), 6.30 (d, 2H), 5.35 (t, 1H), 4.92 (s, 2H), 3.44-3.22 (m,4H), 3.05 (qd, 2H). MS (m/z) 602 [M+H]⁺.

Example 238

Synthesis of ethyl2-(3-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (238B) andethyl 2-(5-(tert-butyl)-3-(trifluoromethyl)-H-pyrazol-1-yl)acetate(238C)

A solution of 1,1,1-trifluoro-5,5-dimethylhexane-2,4-dione (1 g, 5.1mmol) and hydrazine (280 mg, 5.6 mmol) in ethanol, was heated at refluxfor 1 hour. Removed the solvent and used without further purification.To a suspension of crude product and Cs₂CO₃ (1.6 g, 8.3 mmol) in DMF (6mL) was added ethyl bromoacetate as a solution in DMF (5 mL). Thereaction was stirred at room temperature for 5 hrs and then diluted withwater. The mixture was extracted with EtOAc. The organics were driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby SiO₂ chromatography eluting with a gradient of EtOAc in hexanes toprovide 500 mg of 238B and 750 mg of 238C. 238B: MS (m/z) 279 [M+H]⁺.238C: MS (m/z) 279 [M+H]⁺.

Synthesis of provide2-(3-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (238D)

Compound 238D was prepared according to the method presented for thesynthesis of Example 74 substituting 238B for 74B to provide 460 mg oftitle compound. MS (m/z) 251 [M+H]⁺.

Synthesisof(S)-5-(2-(1-(2-(3-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(238E)

Compound 238E was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(3-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (238D)to provide 23 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.68 (dd,1H), 7.64 (dd, 1H), 7.49-7.37 (m, 2H), 7.32 (s, 1H), 7.22 (dd, 1H), 6.67(t, 1H), 6.40 (s, 1H), 6.32 (d, 2H), 5.35 (t, 1H), 5.03 (s, 2H), 3.03(d, 2H), 1.27 (s, 9H). MS (m/z) 604 [M+H]⁺.

Example 239

Synthesis of(S)-5-(2-(1-(2-(5,5-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(239)

Compound 239 was prepared according to the method presented for thesynthesis of Example 150 utilizing 237 and2-(5,5-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)aceticacid to provide 22 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.71(dd, 1H), 7.66 (dd, 1H), 7.46 (dd, 2H), 7.34 (s, 1H), 7.22 (dd, 1H),6.74-6.60 (m, 1H), 6.33 (d, 2H), 5.35 (t, 1H), 4.88 (s, 2H), 3.07 (d,2H). MS (m/z) 624 [M+H]⁺.

Example 240

Synthesis of 22-(5-(difluoromethyl)-3-phenyl-1H-pyrazol-1-yl)acetic acid(240B)

Compound 240B was prepared according to the method presented for thesynthesis of Example 238 substituting4,4-difluoro-1-phenylbutane-1,3-dione for 238A to provide 1.4 g of titlecompound. MS (m/z) 253 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(5-(difluoromethyl)-3-phenyl-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(240C)

Compound 240C was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(5-(difluoromethyl)-3-phenyl-1H-pyrazol-1-yl)acetic acid (240B) toprovide 20 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.69 (dd,1H), 7.63 (dd, 1H), 7.44 (dd, 1H), 7.41-7.34 (m, 5H), 7.22 (dd, 2H),6.92-6.53 (m, 3H), 6.28 (d, 2H), 5.32 (t, 1H), 4.85 (s, 2H), 3.08-2.91(m, 2H). MS (m/z) 606 [M+H]⁺.

Example 241

Synthesis of Provide ethyl2-(3-(difluoromethyl)-5-oxo-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetate(241A)

Compound 241A was prepared according to the method presented for thesynthesis of Example 122 substituting 3-ethoxycyclopent-2-enone for 122Band ethyl 2,2-difluoroacetate for ethyl 2,2,2-trifluoroacetate toprovide 1.6 g of title compound. MS (m/z) 259 [M+H]⁺.

Synthesis of ethyl2-(3-(difluoromethyl)-5,5-difluoro-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetate(241B)

Compound 241B was prepared according to the method presented for thesynthesis of Example 150 substituting 241A for 446 to provide 250 mg oftitle compound. MS (m/z) 281 [M+H]⁺.

Synthesis of2-(3-(difluoromethyl)-5,5-difluoro-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)aceticacid (241C)

Compound 241C was prepared according to the method presented for thesynthesis of Example 74 substituting 241B for 74B to provide 238 mg oftitle compound. MS (m/z) 253 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(3-(difluoromethyl)-5,5-difluoro-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(241D)

Compound 241D was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(3-(difluoromethyl)-5,5-difluoro-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetic acid (241C) to provide 7 mg of title compound: ¹H NMR(400 MHz, cd₃od) δ 8.69 (d, 1H), 7.68-7.57 (m, 1H), 7.52-7.39 (m, 2H),7.32 (s, 1H), 7.27-7.16 (m, 1H), 6.65 (dd, 2H), 6.33 (d, 2H), 5.34 (t,1H), 3.22 (d, 2H), 3.05 (dd, 2H). MS (m/z) 606 [M+H]⁺.

Example 242

Synthesis of ethyl3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylate(242A)

Compound 242A was prepared according to the method presented for thesynthesis of Example 90 substituting bicyclo[3.1.0]hexan-3-one (122B)for 90A to provide 19.4 g of title compound. MS (m/z) 193 [M+H]⁺.

Synthesis of3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carbonitrile(242B)

A suspension of 242A (1 g, 5.62 mmol) in 5 mL of NH₃ (7N in MeOH) washeated at 130° C. in sealed tube overnight. The reaction was monitoredby LC/Mass until complete. Removed the solvent and used as crude.Dissolved the crude product in dioxane (5 mL) and added triethyl amine(4 mL). Trifluoromethanesulfonic anhydride (3.54 g, 16.8 mmol) was addedto the mixture dropwise. The reaction was stirred for 2 hours. Dilutedmixture with EtOAc (100 mL) and washed with aqueous NaHCO₃ twice. Thelayers were separated and the organic layer was washed 2× H₂O and 1×brine. The organics were dried over MgSO₄, filtered and concentrated.The crude product was purified by column chromatography on SiO₂ toprovide 560 mg of title compound. MS (m/z) 146 [M+H]⁺.

Synthesis of ethyl2-(3-cyano-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(242C)

Compound 242C was prepared according to the method presented for thesynthesis of Example 74 substituting 560 mg of 242B for 74A to provide463 mg of title compound. MS (m/z) 232 [M+H]⁺.

Synthesis of5-(2-((1S)-1-(2-(3-cyano-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(242D)

Compound 242D was prepared according to the method presented for thesynthesis of Example 122 substituting 242C for 122D to provide 41 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.63 (dd, 1H), 7.57 (d, 1H),7.48-7.33 (m, 2H), 7.25 (s, 1H), 7.15 (ddd, 1H), 6.68-6.53 (m, 1H), 6.25(d, 2H), 5.26 (td, 1H), 4.75-4.56 (m, 2H), 2.98 (d, 2H), 2.83-2.69 (m,1H), 2.61 (dd, 1H), 2.13-1.99 (m, 2H), 1.05 (dd, 1H), 0.26-0.14 (m, 1H).MS (m/z) 557 [M+H]⁺.

Example 243

Synthesis of 5-(2-((IS)-1-(2-(3-(difluoromethyl)-5-hydroxy-3b,4,4a,5-tetrahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-2-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(243)

Compound 243 was prepared according to the method presented for thesynthesis of Example 154 substituting 220B for 154B to provide 4 mg: ¹HNMR (400 MHz, cd₃od) δ 8.68 (d, 1H), 7.59 (dd, 1H), 7.48-7.32 (m, 2H),7.32-7.13 (m, 2H), 6.87 (dd, 1H), 6.65 (t, 1H), 6.29 (d, 2H), 5.45-5.28(m, 2H), 3.13-2.92 (m, 2H), 2.19 (d, 2H), 1.27 (s, 2H), 1.03 (dd, 1H),0.83 (s, 1H). MS (m/z) 598 [M+H]⁺.

Example 244

Synthesis of2-(5-(tert-butyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (244A)

Compound 244A was prepared according to the method presented for thesynthesis of Example 74 substituting 238C for 74B to provide 450 mg oftitle compound. MS (m/z) 251 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(5-(tert-butyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(244B)

Compound 244B was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(5-(tert-butyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (244A)to provide 22 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.67 (dd,1H), 7.65 (dd, 1H), 7.45 (dd, 1H), 7.39 (d, 1H), 7.31 (s, 1H), 7.23 (dd,1H), 6.71-6.59 (m, 2H), 6.28 (d, 2H), 5.37 (t, 1H), 4.91 (d, 2H), 3.00(d, 2H), 1.29 (s, 9H). MS (m/z) 604 [M+H]⁺.

Example 245F

Synthesis of 3-(2-formylpyridin-3-yl)benzonitrile (245A)

Compound 245A was prepared according to the method presented for thesynthesis of Example 13 utilizing 13A and (3-cyanophenyl)boronic acid toprovide 3.8 g of title compound: MS (m/z) 209 [M+H]⁺.

Synthesis of(S,Z)—N-((3-(3-cyanophenyl)pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(245B)

Compound 245B was prepared according to the method presented for thesynthesis of Example 13 substituting 245A for 13B to provide 4 g oftitle compound: MS (m/z) 312 [M+H]⁺.

Synthesis of(S)—N—((S)-2-(3-chloro-5-fluorophenyl)-1-(3-(3-cyanophenyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide(245C)

Compound 245C was prepared according to the method presented for thesynthesis of Example 13 substituting 245B for 13C and(3-chloro-5-fluorobenzyl)magnesium chloride to provide 1.9 g of titlecompound: MS (m/z) 456 [M+H]⁺.

Synthesis of(S)-3-(2-(1-amino-2-(3-chloro-5-fluorophenyl)ethyl)pyridin-3-yl)benzonitrilehydrochloride (245D)

Compound 245D was prepared according to the method presented for thesynthesis of Example 13 substituting 245C for 13E to provide 70 mg oftitle compound: MS (m/z) 352 [M+H]⁺.

Synthesis of(S)—N-(2-(3-chloro-5-fluorophenyl)-1-(3-(3-cyanophenyl)pyridin-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(245E)

Compound 245E was prepared according to the method presented for thesynthesis of Example 13 substituting 245D for 13F to provide 120 mg oftitle compound: MS (m/z) 525 [M+H]⁺.

Synthesis of(S)-3-(2-(2-(3-chloro-5-fluorophenyl)-1-(2-(5-hydroxy-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(245F)

H₂O₂ (30 wt %, excess) was added to a suspension of 245E (120 mg, 0.19mmol) and potassium carbonate (210 mg, 1.52 mmol) in DMSO (1 mL) at 0°C. The suspension and stirred for 1 hour, filtered and the filtrate waspurified by RP HPLC using a C18 column with a gradient of H₂O, 0.1%TFA-acetonitrile, to provide 80 mg of the title product. ¹H NMR (400MHz, dmso) δ 10.42 (s, 1H), 8.61 (dd, 1H), 8.44 (d, 1H), 7.91 (s, 1H),7.83 (d, 1H), 7.66 (s, 1H), 7.56 (dd, 1H), 7.47-7.25 (m, 4H), 7.02 (d,2H), 6.88 (s, 1H), 6.73 (d, 1H), 6.55 (s, 1H), 6.54-6.43 (m, 2H), 5.16(dd, 2H), 3.36 (s, 2H), 2.88 (d, 2H). MS (m/z) 543 [M+H]⁺.

Example 246

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(6-fluoro-2-oxoindolin-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(246)

Compound 246 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(6-fluoro-2-oxoindolin-3-yl)acetic acid to provide 13 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.62 (d, 1H), 7.64-7.53 (m, 1H),7.43-7.33 (m, 1H), 7.31-7.00 (m, 3H), 6.95-6.79 (m, 1H), 6.68-6.35 (m,3H), 6.30-6.12 (m, 2H), 5.24 (dd, 1H), 3.62 (s, 1H), 3.01-2.72 (m, 3H),2.65-2.49 (m, 1H). MS (m/z) 563 [M+H]⁺.

Example 247

Synthesis of2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-N—((S)-2-(3,5-difluorophenyl)-1-(3-(4-ethoxyphenyl)pyridin-2-yl)ethyl)acetamide(247)

Compound 247 was prepared according to the method presented for thesynthesis of Example 68 utilizing 68A and (4-ethoxyphenyl)boronic acidto provide 8 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.61 (d,1H), 7.61 (d, 1H), 7.40 (dd, 4.9 Hz, 1H), 7.03-6.94 (m, 2H), 6.90 (dd,2H), 6.86-6.51 (m, 3H), 6.25 (d, 2H), 5.48 (d, 1H), 4.05 (q, 2H), 2.96(t, 2H), 2.46 (s, 2H), 1.39 (t, 4H), 1.07 (s, 1H). MS (m/z) 601 [M+H]⁺.

Example 248

Synthesis of 5-(2-((1S)-1-(2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(248)

248 was separated from the diastereomeric mixture of 198 bysemi-preparative chiral HPLC fitted with a Chiralcel AZ-H column runninga 70:30 mixture of Hep:IPA. The fast eluent was collected to obtain 3 mgof the single diastereomer: ¹H NMR (400 MHz, cd₃od) δ 8.50 (dd, 1H),7.46 (dd, 1H), 7.34-7.10 (m, 3H), 7.04 (dd, 8.5 Hz, 1H), 6.58-6.23 (m,2H), 6.11 (t, 2H), 5.15 (t, 1H), 4.57-4.38 (m, 2H), 2.93-2.79 (m, 2H),2.59 (dd, 1H), 2.43 (d, 1H), 1.99-1.77 (m, 2H), 0.86 (td, 1H), 0.01 (dd,1H). MS (m/z) 582 [M+H]⁺.

Example 249

Synthesis of5-(2-((1S)-1-(2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(249)

249 was separated from the diastereomeric mixture of 198 bysemi-preparative chiral HPLC fitted with a Chiralcel AZ-H column runninga 70:30 mixture of Hep:IPA. The slow eluent was collected to obtain 3 mgof the single diastereomer: ¹H NMR (400 MHz, cd₃od) δ 8.47 (dd, 1H),7.40 (dd, 1H), 7.21 (dd, 2H), 7.10 (s, 1H), 7.01 (dd, 1H), 6.54-6.20 (m,2H), 6.11 (d, 2H), 5.12 (t, 1H), 4.54-4.37 (m, 2H), 2.93-2.72 (m, 2H),2.58 (dd, 1H), 2.44 (d, 1H), 1.86 (dd, 2H), 0.85 (td, 1H), 0.02 (dd,1H). MS (m/z) 582 [M+H]⁺.

Example 250

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(250)

Compound 250 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(3-(trifluoromethyl)-1H-indazol-1-yl)acetic acid to provide 36 mg oftitle compound: ¹H NMR (400 MHz, dmso) δ 9.13 (d, 1H), 8.71 (dd, 1H),7.73 (d, 1H), 7.67-7.55 (m, 3H), 7.52-7.35 (m, 4H), 7.28 (ddd, 2H), 6.92(t, 1H), 6.57 (d, 2H), 5.27-5.09 (m, 3H), 3.03 (d, 2H). MS (m/z) 598[M+H]⁺.

Example 251

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(251)

Compound 251 was prepared according to the method presented for thesynthesis of Example 200 substituting 227 for 200A to provide 7 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd, 1H), 7.58 (dd, 2H),7.40 (dd, 1H), 7.19 (t, 2H), 6.66 (tt, 1H), 6.33 (t, 2H), 5.32 (dd, 1H),4.96 (s, 2H), 4.51 (s, 2H), 4.46 (s, 2H), 3.08 (qd, 2H). MS (m/z) 589[M+H]⁺.

Example 252

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-isopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(252)

Compound 252 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(5-isopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid (236B) toprovide 18 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd,1H), 7.65 (dd, 1H), 7.45 (dd, 2H), 7.33 (s, 1H), 7.22 (dd, 1H), 6.67 (t,1H), 6.40 (s, 1H), 6.34 (d, 2H), 5.36 (t, 1H), 4.90 (s, 2H), 3.06 (d,2H), 2.83 (dt, 1H), 1.17 (t, 6H). MS (m/z) 590 [M+H]⁺.

Example 253

Synthesis of2-fluoro-5-(2-((1S)-1-(2-(5-fluoro-2-oxoindolin-3-yl)acetamido)-2-(3-fluorophenyl)ethyl)pyridin-3-yl)benzamide(253)

Compound 253 was prepared according to the method presented for thesynthesis of Example 59 utilizing 59D and2-(5-fluoro-2-oxoindolin-3-yl)acetic acid to provide 21 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.62 (ddd, 1H), 7.56 (ddd, 1H),7.45-7.24 (m, 2H), 7.22-6.80 (m, 51H), 6.73 (ddd, 2H), 6.43 (t, 1H),6.40-6.32 (m, 1H), 5.23 (dt, 1H), 3.89-3.74 (m, 1H), 3.03-2.88 (m, 2H),2.66-2.54 (m, 2H). MS (m/z) 545 [M+H]⁺.

Example 254

Synthesis of 5-(2-((1S)-1-(2-(3-cyano-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(254)

Compound 254 was prepared according to the method presented for thesynthesis of Example 181 substituting 242C for 122D to provide 28 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.72 (dd, 1H), 7.67 (d, 1H),7.48 (dd, 1H), 7.34 (d, 2H), 7.27-7.16 (m, 1H), 6.67 (t, 1H), 6.31 (d,2H), 5.34 (t, 1H), 4.90 (s, 2H), 3.06 (dd, 2H), 2.52 (d, 2H), 1.42 (dd,1H), 1.11 (s, 1H). MS (m/z) 593 [M+H]⁺.

Example 255

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(6-methyl-2-oxoindolin-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(255)

Compound 225 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(6-methyl-2-oxoindolin-3-yl)acetic acid to provide 7 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.71 (t, 1H), 7.75-7.66 (m, 1H),7.50 (td, 1H), 7.46-7.09 (m, 3H), 7.08-6.52 (m, 5H), 6.29 (t, 2H), 5.32(dd, 1H), 3.66 (d, 1H), 3.06-2.93 (m, 2H), 2.93-2.56 (m, 3H), 2.23 (d,3H). MS (m/z) 559 [M+H]⁺.

Example 256

Synthesis of5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(6-methoxy-2-oxoindolin-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(256)

Compound 256 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(6-methoxy-2-oxoindolin-3-yl)acetic acid to provide 19 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.68 (dd, 1H), 7.61 (dd, 1H),7.53-7.34 (m, 2H), 7.34-7.08 (m, 2H), 7.03 (d, 1H), 6.74-6.57 (m, 1H),6.56-6.22 (m, 4H), 5.31 (dt, 1H), 3.91-3.70 (m, 4H), 3.13-2.89 (m, 2H),2.76-2.58 (m, 2H). MS (m/z) 575 [M+H]⁺.

Example 257

Synthesis of(S)-2-fluoro-5-(2-(2-(3-fluorophenyl)-1-(2-(2-oxo-1,2-dihydroquinolin-4-yl)acetamido)ethyl)pyridin-3-yl)benzamide(257)

Compound 257 was prepared according to the method presented for thesynthesis of Example 59 utilizing 59D and2-(2-oxo-1,2-dihydroquinolin-4-yl)acetic acid to provide 15 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.73 (dd, 1H), 7.67 (dd, 2H),7.56-7.45 (m, 2H), 7.40-7.24 (m, 3H), 7.23-7.10 (m, 2H), 7.04 (dd, 1H),6.81 (dd, 1H), 6.60-6.41 (m, 3H), 5.33 (t, 1H), 3.85 (s, 2H), 3.13-3.02(m, 2H). MS (m/z) 539 [M+H]⁺.

Example 258

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,6-dihydro-1H-furo[3,4-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(258)

Compound 258 was prepared according to the method presented for thesynthesis of Example 122 substituting 203C for 122D to provide 42 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd, 1H), 7.63 (dd, 1H),7.54-7.39 (m, 2H), 7.31 (s, 1H), 7.22 (dd, 1H), 6.66 (t, 1H), 6.32 (d,2H), 5.34 (t, 1H), 4.90-4.84 (m, 4H), 4.78 (d, 2H), 3.16-2.97 (m, 2H).MS (m/z) 590 [M+H]⁺.

Example 259

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(4,7-dimethyl-2-oxoindolin-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(259)

Compound 259 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(4,7-dimethylindolin-3-yl)acetic acid to provide 21 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.76-8.65 (m, 1H), 7.62 (dd, 1H),7.46 (dd, 1H), 7.12 (ddd, 3H), 6.93-6.57 (m, 4H), 6.29 (dd, 3H),5.30-5.15 (m, 1H), 3.69 (d, 1H), 3.14-2.82 (m, 5H), 2.15 (d, 6H). MS(m/z) 573 [M+H]⁺.

Example 260

Synthesis of5-(2-((1S)-1-(2-(3-(difluoromethyl)-5-fluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(260)

Compound 260 was prepared according to the method presented for thesynthesis of Example 390 substituting 212 for 334 to provide 18 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.73-8.55 (m, 1H), 7.67-7.53(m, 1H), 7.50-7.08 (m, 4H), 6.78-6.37 (m, 2H), 6.22 (td, 2H), 6.14-5.86(m, 1H), 5.46 (dd, 1H), 5.25 (ddd, 1H), 3.03-2.85 (m, 2H), 2.36-2.10 (m,2H), 1.21 (dd, 1H), 1.12-0.84 (m, 1H), 0.39-0.15 (m, 1H). MS (m/z) 600[M+H]⁺.

Example 261

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,6-dihydro-2H-thieno[3,4-c]pyrazol-2-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(261)

Compound 261 was prepared according to the method presented for thesynthesis of Example 122 substituting 189B for 122D to provide toprovide 31 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.73-8.59 (m,1H), 7.53 (dd, 1H), 7.49-7.26 (m, 3H), 7.26-7.15 (m, 1H), 6.63 (t, 1H),6.37-6.23 (m, 2H), 5.35 (t, 1H), 4.88 (d, 1H), 4.00-3.78 (m, 4H),3.15-2.89 (m, 2H). MS (m/z) 606 [M+H]⁺.

Example 262

Synthesis of 3-bromo-N-methoxy-N,5-dimethylpicolinamide (262B)

A solution of 262A (1 g, 4.63 mmol) in oxalyl chloride (5 mL) was heatedat 60° C. for 30 minutes. Removed the solvent and dissolved in DCM (10mL). Cooled mixture to 0° C. N,O-Dimethylhydroxylamine hydrochloride(0.57 g, 5.84 mmol) and DIEA (1.61 mL, 9.26 mmol) were added to themixture slowly. After 1 hour, diluted the reaction with EtOAc (50 mL)and washed with brine (20 mL) twice. The organic layer was dried withNa₂SO₄, concentrated and purified by flash column (Rf: 0.3EtOAc/Hexanes=40%) to provide 1.07 g of title compound. MS (m/z) 259[M+H]⁺.

Synthesis of 3-bromo-5-methylpicolinaldehyde (262C)

A solution of 262B (1.7 g, 3.7 mmol) in tetrahydrofuran (20 mL) at −78°C., LiAlH4 (5.55 mL, 1M in THF) was added to a solution dropwise. Themixture was stirred for 3 hours at −78° C. Acidified by 1N_hydrochloridein methanol at −78° C. and warmed up to r.t. The mixture was extractedwith EtOAc (50 mL) twice. The organic layer was dried with Na₂SO₄,concentrated and purified by flash column (Rf: 0.3 EtOAc/Hexanes=5%) toprovide 0.83 g of title compound. MS (m/z) 200 [M+H]⁺.

Synthesis of(S)—N-(1-(3-bromo-5-methylpyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(262F)

Compound 262F was prepared according to the method presented for thesynthesis of Example 38 substituting 262C (0.83, 3.7 mmol) for 38A toprovide 360 mg of title compound: MS (m/z) 500 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-1H-indol-3-yl)acetamido)ethyl)-5-methylpyridin-3-yl)-2-fluorobenzamide(262G)

262F (48.7 mg, 0.1 mmol), potassium carbonate (27 mg, 0.2 mmol) in 0.5ml of water, tetrakis(triphenylphosphine) palladium(0) (8 mg, 0.007mmol) and 3-cyanophenylboronic acid (0.12 mmol) in DME (1.5 mL) washeated to 120° C. for 30 minutes under microwave irradiation. Solventswere concentrated in vacuo and the residue was purified by RP HPLC usinga C18 column with a gradient of 0.1% TFA-acetonitrile in 0.1% TFA/H₂O toprovide 7.5 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.38 (s,1H), 7.56 (s, 1H), 7.43 (s, 1H), 7.33-7.11 (m, 3H), 7.06 (s, 1H), 6.72(d, 1H), 6.66 (d, 2H), 6.26 (d, 2H), 5.47 (s, 2H), 5.36-5.22 (m, 1H),3.59 (d, 2H), 3.05-2.85 (m, 2H), 2.38 (s, 3H); MS (m/z) 559 [M+H]⁺

Example 263

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5,5-dioxido-3-(trifluoromethyl)-6,7-dihydrothiopyrano[4,3-c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(263)

Compound 263 was prepared according to the method presented for thesynthesis of Example 197 to provide 25 mg of title compound: ¹H NMR (400MHz, cd₃od) δ 8.33 (d, 1H), 7.51-7.08 (m, 5H), 6.64 (t, 1H), 6.34 (d,2H), 5.38 (dd, 1H), 4.95-4.81 (m, 2H), 4.19 (s, 2H), 3.57-3.43 (m, 1H),3.31 (d, 2H), 3.17-2.94 (m, 3H). MS (m/z) 652 [M+H]⁺.

Example 264

Synthesis of(S)-2-fluoro-5-(2-(2-(3-fluorophenyl)-1-(2-(3-oxo-3,4-dihydroquinoxalin-1(2H)-yl)acetamido)ethyl)pyridin-3-yl)benzamide(264)

Compound 264 was prepared according to the method presented for thesynthesis of Example 59 utilizing 59D and2-(3-oxo-3,4-dihydroquinoxalin-1(2H)-yl)acetic acid to provide 18 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.73-8.59 (m, 1H), 7.63 (dd,1H), 7.44 (ddd, 1H), 7.36-7.16 (m, 2H), 7.17-6.95 (m, 2H), 6.77 (t, 2H),6.70-6.50 (m, 2H), 6.43 (dd, 2H), 5.29 (dd, 1H), 4.49 (d, 1H), 3.78 (s,1H), 3.08-2.89 (m, 2H). MS (m/z) 542 [M+H]⁺.

Example 265

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(265)

Compound 265 was prepared according to the method presented for thesynthesis of Example 325 substituting 237 for 325 to provide 19 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.71 (dd, 1H), 7.75-7.62 (m,1H), 7.55-7.40 (m, 2H), 7.31 (s, 1H), 7.27-7.15 (m, 1H), 6.67 (td, 1H),6.42-6.23 (m, 2H), 5.36 (td, 1H), 4.95 (ddd, 1H), 4.81 (d, 2H),3.15-2.94 (m, 4H), 2.65-2.50 (m, 2H). MS (m/z) 604 [M+H]⁺.

Example 266

Synthesis of 2ethyl 2-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate(266B)

Compound 266B was prepared according to the method presented for thesynthesis of Example 74 substituting2-chloro-7H-pyrrolo[2,3-d]pyrimidine (266A) for1-7,8,8-trimethyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-4,7-methanoindazole(74A) to provide 480 mg of title compound. MS (m/z) 240 [M+H]⁺.

Synthesis of(S)-3-(2-(1-(2-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(266C)

Compound 266C was prepared according to the method presented for thesynthesis of Example 50 utilizing 50C and2-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetic acid (266B) toprovide 5 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.72 (d, 1H),8.66 (dd, 1H), 7.78 (d, 1H), 7.68 (dd, 1H), 7.51 (s, 1H), 7.45 (dd, 1H),7.41-7.30 (m, 2H), 7.22 (d, 1H), 6.67-6.50 (m, 2H), 6.18 (d, 2H), 5.36(dd, 1H), 5.04-4.86 (m, 2H), 2.98 (d, 2H). MS (m/z) 547 [M+H]⁺.

Example 267

Synthesis of5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5-fluoro-2-oxoindolin-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(267)

Compound 267 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(5-fluorol-2-oxoindolin-3-yl)acetic acid to provide 19 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.77-8.62 (m, 1H), 7.60 (dd, 1H),7.53-7.31 (m, 2H), 7.31-7.21 (m, 1H), 7.20-6.97 (m, 1H), 6.96-6.77 (m,2H), 6.65 (dd, 1H), 6.31 (t, 2H), 5.33 (dt, 1H), 3.90 (dt, 1H),3.15-2.88 (m, 2H), 2.67 (dd, 2H); MS (m/z) 563 [M+H]⁺

Example 268

Synthesis ofN—((S)-1-(3-(4-cyclopropoxyphenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(268)

Compound 268 was prepared according to the method presented for thesynthesis of Example 68 utilizing 68A and (4-cyclopropoxyphenyl)boronicacid to provide 14 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.62(d, 1H), 7.73-7.61 (m, 1H), 7.45 (dd, 1H), 7.10-6.95 (m, 4H), 6.68 (ddd,2H), 6.25 (d, 2H), 5.49 (d, 1H), 3.79 (s, 1H), 2.97 (t, 2H), 2.46 (d,2H), 1.36 (s, 1H), 1.07 (s, 1H), 0.86-0.65 (m, 4H). MS (m/z) 613 [M+H]⁺.

Example 269

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-oxo-3,4-dihydroquinoxalin-1(2H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide (269)

Compound 269 was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(3-oxo-3,4-dihydroquinoxalin-1(2H)-yl)acetic acid to provide 14 mg oftitle compound: ¹H NMR (400 MHz, cd₃od) δ 8.79-8.70 (m, 1H), 7.89-7.68(m, 2H), 7.63-7.33 (m, 4H), 7.30-7.13 (m, 2H), 6.85 (dd, 1H), 6.80-6.55(m, 3H), 6.36 (d, 2H), 5.39 (dd, 1H), 4.60 (s, 1H), 3.87 (d, 1H),3.19-2.99 (m, 2H). MS (m/z) 560 [M+H]⁺.

Example 270

Synthesis of ethyl2-(4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)acetate(270A)

To a mixture of 535C (200 mg, 0.72 mmol) in methanesulfonic acid (0.86mL) and DCM (1.2 mL), sodium azide (65 mg, 1 mmol) was added and themixture was stirred overnight. Diluted with DCM (30 mL) and washed withNaHCO₃(aq) twice. The organics were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by SiO₂ chromatographyeluting with a gradient of EtOAc in hexanes to provide 40 mg of titlecompound. MS (m/z) 292 [M+H]⁺.

Synthesis of2-(4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)aceticacid (270B)

Compound 270B was prepared according to the method presented for thesynthesis of Example 74 substituting 270A for 74B to provide 30 mg oftitle compound. MS (m/z) 264 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(270C)

Compound 270C was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and2-(4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)aceticacid to provide 42 mg of title compound: ¹H NMR (400 MHz, cd₃od) δ 8.72(dd, 1H), 7.67 (dd, 1H), 7.47 (dd, 2H), 7.31 (s, 1H), 7.22 (dd, 1H),6.76-6.60 (m, 1H), 6.34 (d, 2H), 5.36 (t, 1H), 4.95 (s, 2H), 3.52 (t,2H), 3.10 (t, 2H), 2.96-2.77 (m, 2H). MS (m/z) 617 [M+H]⁺.

Example 271

Synthesis of 2-(5-fluoro-3-(trifluoromethyl)-1H-indazol-1-yl)acetic acid(271A)

Compound 271A was prepared according to the method presented for thesynthesis of Example 74 substituting 199D for 74B to provide 52.6 mg oftitle compound. MS (m/z) 263 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-fluoro-3-(trifluoromethyl)-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(271B)

Compound 271B was prepared according to the method presented for thesynthesis of Example 54 utilizing 54B and 271A to provide 76 mg of titlecompound: ¹H NMR (400 MHz, cd₃od) δ 8.72 (dd, 1H), 7.67 (dd, 1H), 7.55(dd, 1H), 7.52-7.38 (m, 3H), 7.38-7.24 (m, 2H), 7.19 (dd, 1H), 6.66(ddd, 1H), 6.33 (t, 2H), 5.36 (t, 1H), 5.24 (s, 2H), 3.08 (d, 2H). MS(m/z) 616 [M+H]⁺.

Example 272

Synthesis of ethyl2-(4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(272A)

Ethyl 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(4.9 g. 17.7 mmol) was dissolved in 170 mL of acetic acid. To it wasadded chromium trioxide (2.65 g, 26.5 mmol) and the resulting mixturewas stirred at ambient temperature for 3 days. To it was added morechromium trioxide (885 mg, 8.85 mmol) and the reaction was allowed tostir for one day. It was then quenched with 2-propanol at 0° C. and thesolvent was removed in vacuo. The residue was partitioned between EtOAcand water. The organic layer was separated, washed with half brine,dried over MgSO₄ and filtered. The filtrate was concentrated andpurified by silica gel chromatography eluting with EtOAc and hexanes toafford 1.78 g of 272B and 1.94 g of the title compound. MS (m/z) 291.16[M+H]⁺.

Synthesis of ethyl2-(4-methylene-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(272C)

Ethyl2-(4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(600 mg, 2 mmol) was dissolved in 20 mL of THF and 4 mL of pyridine. Toit at 0° C. was slowly added 2 mL of Tebbe reagent (0.5 M in toluene, 3mmol) and the reaction mixture was stirred at ambient temperature for 3hours. More Tebbe reagent (0.5 M in toluene, 3 mmol) was added and thereaction was allowed to stir for 3 days. It was quenched at 0° C. withNaHCO₃ (saturated aqueous solution), and filtered through a pad ofcelite. The filtrate was partitioned between EtOAc and water. Theorganic layer was separated, washed with half brine, dried over MgSO₄and filtered. The filtrate was concentrated and purified by silica gelchromatography eluting with EtOAc and hexanes to afford 45 mg of thetitle compound. MS (m/z) 289.10 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-methylene-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(272D) and(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-methyl-3-(trifluoromethyl)-6,7-dihydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(272E)

The mixture of Compound 272D and Compound 272E was prepared according tothe method presented in the synthesis of Example 60 utilizing Compound54B and ethyl2-(4-methylene-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetateto afford the title compounds. MS (m/z) 614.22 [M+H]⁺.

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(4-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(272F)

The mixture of 272D and 272E (7.2 mg) was dissolved in 10 mL of EtOAc.The system was purged with argon, and then Rh/Al (5%, 5 mg) was added.The reaction was stirred under 1 atm H₂ at ambient temperature for 16hours. Upon completion of the reaction, it was filtered through a pad ofcelite and washed with EtOAc. The filtrate was collected and thevolatiles were removed in vacuo. The residue was purified by reversephase HPLC eluting with acetonitrile/water (with 0.1% TFA) to afford 3.4mg of the title compound. MS (m/z) 616.19 [M+H]⁺. ¹H NMR (400 MHz,cd₃od) δ 8.61 (dd, J=4.8, 1.5 Hz, 1H), 7.55 (dd, J=7.8, 1.5 Hz, 1H),7.42-7.33 (m, 2H), 7.27 (s, 1H), 7.15 (dd, J=10.7, 8.5 Hz, 1H), 6.59 (t,J=9.1 Hz, 1H), 6.27 (d, J=8.1 Hz, 2H), 5.29 (t, J=7.5 Hz, 1H), 4.70 (s,2H), 2.98 (d, J=8.1 Hz, 2H), 2.85 (d, J=5.8 Hz, 1H), 2.47-2.14 (m, 2H),1.92-1.63 (m, 3H), 1.54-1.43 (m, 1H), 1.10 (d, J=6.9 Hz, 3H).

Example 273

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(7-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(273)

Compound 273 was prepared (11 mg) according to the method presented inthe synthesis of Example 60 utilizing Compound 54B and Compound 272B toprovide the title compound: MS (m/z) 616.43 [M+H]⁺. ¹H NMR (400 MHz,cd₃od) δ 8.75 (dd, J=5.0, 1.6 Hz, 1H), 7.73 (dd, J=7.8, 1.6 Hz, 1H),7.53 (dd, J=7.8, 5.0 Hz, 1H), 7.45-7.28 (m, 2H), 7.20 (dd, J=10.7, 8.6Hz, 1H), 6.66 (tt, J=9.2, 2.3 Hz, 1H), 6.31 (d, J=6.1 Hz, 2H), 5.36 (dd,J=8.4, 6.7 Hz, 1H), 5.24 (s, 2H), 3.18-3.02 (m, 2H), 2.85 (t, J=5.9 Hz,2H), 2.60-2.47 (m, 2H), 2.25-2.03 (m, 2H).

Example 274

Synthesis of (S)-tert-butyl1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-3-(trifluoromethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(274)

Compound 274 was prepared (7 mg) according to the method presented inthe synthesis of Example 56 utilizing 56A and tert-butyl3-(trifluoromethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylateto provide the title compound. MS (m/z) 703.16 [M+H]⁺. ¹H NMR (400 MHz,cdcl₃) δ 8.56 (d, J=4.8 Hz, 1H), 7.64 (d, J=5.7 Hz, 1H), 7.48 (d, J=7.0Hz, 1H), 7.38 (s, 1H), 7.33-7.28 (m, 1H), 7.18 (dd, J=11.1, 8.5 Hz, 1H),6.77 (s, 1H), 6.54 (t, J=9.1 Hz, 1H), 6.11 (d, J=6.1 Hz, 2H), 5.86 (s,1H), 5.42 (dd, J=14.9, 7.7 Hz, 1H), 4.70 (s, 2H), 4.51 (s, 2H), 3.69 (s,2H), 2.85 (dd, J=16.0, 8.2 Hz, 2H), 2.61 (d, J=5.3 Hz, 2H), 1.48 (d,J=7.8 Hz, 9H).

Example 275

Synthesis of(S)-5-(2-(1-(2-(4-bromo-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(275)

Compound 275 was prepared (6 mg) according to the method presented inthe synthesis of Example 56 utilizing Compound 56A and4-bromo-5-methyl-3-(trifluoromethyl)-1H-pyrazole to provide the titlecompound. MS (m/z) 641.32 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.69 (dd,J=4.7, 1.6 Hz, 1H), 7.56 (dd, J=7.8, 1.7 Hz, 1H), 7.46-7.27 (m, 3H),7.21 (dd, J=10.7, 8.5 Hz, 1H), 6.65 (t, J=9.2 Hz, 1H), 6.32 (d, J=6.3Hz, 2H), 5.40-5.25 (m, 1H), 4.92 (s, 2H), 3.06 (qd, J=13.3, 7.8 Hz, 2H),2.17 (s, 3H).

Example 276

Synthesis of(S)-5-(2-(1-(2-(4-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(276)

To the mixture of(S)-5-(2-(1-(2-(4-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(463, 20 mg, 0.03 mmol), cyclopropane boronic acid (8.2 mg, 0.09 mmol)and potassium phosphate tribasic (25 mg, 0.12 mmol) were added 1 mL oftoluene and 2 drops of water. After the system was purged with argon,palladium (II) acetate (2 mg, 0.003 mmol) and tricyclohexylphosphine (2mg, 0.006 mmol) was added and the reaction mixture was heated up to 120°C. for 3 hours. The solvent was removed and the residue was purified byreverse phase HPLC eluting with acetonitrile/water (with 0.1% TFA) toafford 6.5 mg of the title compound. MS (m/z) 588.35 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.68 (dd, J=4.8, 1.6 Hz, 1H), 7.64 (dd, J=7.8, 1.6 Hz,1H), 7.49-7.29 (m, 4H), 7.22 (dd, J=10.7, 8.5 Hz, 1H), 6.65 (t, J=9.2Hz, 1H), 6.30 (d, J=6.3 Hz, 2H), 5.33 (t, J=7.5 Hz, 1H), 4.83 (s, 1H),3.04 (d, J=7.7 Hz, 2H), 1.72 (m, 1H), 1.01-0.76 (m, 2H), 0.62-0.45 (m,2H).

Example 277

Synthesis of ethyl2-(3′-(trifluoromethyl)-6′,7′-dihydrospiro[cyclopropane-1,4′-indazole]-1′(5′H)-yl)acetate(277A)

Dichloromethane (3 mL) was added to diethylzinc (1.0 M hexane solution,1.56 mL, 1.56 mmol), and then a solution of TFA (48 μL, 0.6 mmol) indichloromethane (2 mL) was slowly added at 0° C. The reaction mixturewas stirred for 20 min, and then a solution of diiodomethane (125 μL,1.5 mmol) in dichloromethane (2 mL) was added dropwise. The reactionmixture was stirred for 20 min, and then a solution of ethyl2-(4-methylene-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(272, 45 mg, 0.15 mmol) in dichloromethane (1.5 mL) was added and thereaction was allowed to stir at ambient temperature for 16 hours.Dichloromethane and saturated aqueous ammonium chloride solution wereadded to the reaction mixture and the organic layer was separated andthe aqueous layer was extracted by dichloromethane one more time. Thecombined organic layer was dried over sodium sulfate anhydrous, filteredand concentrated. The residue was purified by silica gel chromatographyeluting with EtOAc and hexane to afford 21 mg of the title compound. MS(m/z) 303.20 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3′-(trifluoromethyl)-6′,7′-dihydrospiro[cyclopropane-1,4′-indazole]-1′(5′H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(277B)

Compound 277B was prepared (27 mg) according to the method presented inthe synthesis of Example 60 utilizing Compound 54B and ethyl2-(3′-(trifluoromethyl)-6′,7′-dihydrospiro[cyclopropane-1,4′-indazole]-1′(5′H)-yl)acetateto provide the title compound. MS (m/z) 628.5 [M+H]⁺. ¹H NMR (400 MHz,cd₃od) δ 8.71 (dd, J=4.9, 1.6 Hz, 1H), 7.71 (dd, J=7.8, 1.6 Hz, 1H),7.48 (ddd, J=9.2, 7.3, 3.6 Hz, 2H), 7.37 (s, 1H), 7.24 (dd, J=10.7, 8.5Hz, 1H), 6.68 (tt, J=9.2, 2.2 Hz, 1H), 6.36 (t, J=6.2 Hz, 2H), 5.38 (t,J=7.6 Hz, 1H), 4.79 (s, 2H), 3.21-2.94 (m, 2H), 2.63-2.39 (m, 2H),2.02-1.76 (m, 2H), 1.64-1.42 (m, 2H), 1.08-0.87 (m, 2H), 0.63 (t, J=5.2Hz, 2H).

Example 278

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(278)

Compound 278 was prepared (13 mg) according to the method presented inthe synthesis of Example 55 utilizing Compound 55D and2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid, and then Suzukicoupling with 3-carbamoylphenylboronic acid to afford the titlecompound. MS (m/z) 540.2 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.23 (s, 1H),8.74 (d, J=4.8 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.71-7.55 (m, 3H),7.53-7.39 (m, 3H), 7.29 (d, J=7.7 Hz, 1H), 6.66 (m, 1H), 6.30 (d, J=6.4Hz, 2H), 5.45 (t, J=7.5 Hz, 1H), 5.26 (s, 2H), 3.18-2.96 (m, 2H), 2.44(d, J=6.9 Hz, 6H).

Example 279

Synthesis of 5-bromo-N-methoxy-N-methylpyrimidine-4-carboxamide (279A)

5-bromopyrimidine-4-carboxylic acid (5 g, 24.6 mmol) andN,O-dimethylhydroxylamine hydrochloride (3.6 g, 36.9 mmol) weredissolved in 100 mL of CH₂Cl₂ and to it was addedN,N-diisopropylethylamine (21 mL, 123 mmol). The reaction mixture wascooled down to 0° C. and to it was added HATU (11.2 g, 29.5 mmol). Thereaction mixture was allowed to stir at 0° C. for 30 min. it was thendiluted with CH₂Cl₂ and washed with half brine. The organic layer wasseparated, dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by silica gel chromatography eluting withEtOAc/hexanes to afford 5.84 g of the title compound. MS (m/z): 248.1[M+H]⁺.

Synthesis of 5-bromopyrimidine-4-carbaldehyde (279B)

5-bromo-N-methoxy-N-methylpyrimidine-4-carboxamide (2.45 g, 10 mmol) wasdissolved in 50 mL of THF and cooled down to −10° C. DIBAL (1.0 M intoluene, 15 mL, and 15 mmol) was added slowly to keep internaltemperature at −10° C. After addition, the reaction was quenched withiPrOH and 1N HCl. The mixture was partitioned between EtOAc and brine.The organic layer was separated, dried over MgSO₄, filtered andconcentrated to afford 1.19 g of the title compound. MS (m/z): 187.2[M+H]⁺.

Synthesis ofN-((5-bromopyrimidin-4-yl)methylene)-2-methylpropane-2-sulfinamide(279C)

Compound 279C was prepared according to the method presented for thesynthesis of Example 13C substituting Compound 279B for3-(4-methoxyphenyl)picolinaldehyde to provide the title compound: MS(m/z) 292.0 [M+H]⁺.

Synthesis of(R)—N—((R)-1-(5-bromopyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(279E)

(3,5-difluorobenzyl)magnesium bromide (0.25 M in ether, 20 mL, 5 mmol)was added dropwise to a solution ofN-((5-bromopyrimidin-4-yl)methylene)-2-methylpropane-2-sulfinamide (730mg, 2.5 mmol) and copper (II) triflate (45 mg, 0.125 mmol) in CH₂Cl₂ (15mL) at −78° C. After addition, ammonium chloride (aq, 10 ml) was addedto the reaction and the mixture was allowed to warm up to ambienttemperature. It was extracted with EtOAc (2×30 mL). The organic layerwas dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by flash column to afford 136 mg of(R)—N—((S)-1-(5-bromopyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(279D) and 355 mg of the title compound: MS (m/z) 419.8 [M+H]⁺

Synthesis of(R)-1-(5-bromopyrimidin-4-yl)-2-(3,5-difluorophenyl)ethanaminehydrochloride (279F)

(R)—N—((R)-1-(5-bromopyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(766 mg, 1.8 mmol) was dissolved in 5 mL of methanol and to it was addedHCl solution (4N in dioxane, 1.8 mL). After stirring at ambienttemperature for 10 min, diethyl ether was added and the mixture wasallowed to stir for 1 hour. The resulting precipitate was collected byvacuum filtration and then dried under high vacuum to provide 554 mg ofthe title compound: MS (m/z) 316.2 [M+H]⁺.

Synthesis(R)—N-(1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetamide(279G)

Compound 279G was prepared (11 mg) according to the method presented inthe synthesis of Example 57 utilizing Compound 279F and2-(5,6-dimethyl-H-benzo[d]imidazol-1-yl)acetic acid, and then Suzukicoupling with 4-chlorophenylboronic acid to afford the title compound.MS (m/z) 532.3 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.23 (d, J=15.1 Hz,2H), 8.54 (s, 1H), 7.59 (s, 1H), 7.51-7.35 (m, 3H), 7.18 (d, J=8.1 Hz,2H), 6.74 (m, 1H), 6.38 (d, J=6.8 Hz, 2H), 5.45 (d, J=7.5 Hz, 1H), 5.25(s, 2H), 3.08 (t, J=7.1 Hz, 2H), 2.45 (s, 6H).

Example 280

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-(3,3-dimethylbut-1-ynyl)-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(280)

(S)-5-(2-(1-(2-(4-bromo-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(58, 40 mg, 0.06 mmol) was dissolved in 2 mL of DMF and 0.4 mL oftriethylamine. The system was degassed and purged with argon. To it wasadded copper(I) iodide (2.2 mg, 0.012 mmol) andbis(triphenylphosphine)palladium(II) chloride (4.2 mg, 0.006 mmol). Thesystem was purged with argon again. 3,3-dimethylbut-1-yne (37 μL, 0.3mmol) was added and the mixture was heated up to 85° C. for 16 hours andthen added more 3,3-dimethylbut-1-yne (74 μL, 0.6 mmol), copper(I)iodide (2.2 mg, 0.012 mmol) and bis(triphenylphosphine)palladium(II)chloride (4.2 mg, 0.006 mmol). The mixture was heated up to 180° C. for16 hours. It was cooled down and filtered through a pad of celite andwashed with EtOAc. The filtrate was washed with 5% LiCl aqueoussolution, water (20 mL with 1 mL of ammonia) and brine. The organiclayer was separated, washed with half brine, dried over MgSO₄ andfiltered. The filtrate was concentrated and purified by reverse phaseHPLC eluting with acetonitrile/water (with 0.1% TFA) to afford 6 mg ofthe title compound. MS (m/z) 657.10 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ8.69 (dd, J=4.8, 1.6 Hz, 1H), 7.60 (dd, J=7.8, 1.6 Hz, 1H), 7.41 (dd,J=7.8, 4.8 Hz, 2H), 7.31 (s, 1H), 7.21 (dd, J=10.7, 8.5 Hz, 1H), 6.66(t, J=9.2 Hz, 1H), 6.33 (d, J=6.3 Hz, 2H), 5.34 (t, J=7.5 Hz, 1H), 4.86(s, 2H), 3.13-2.96 (m, 2H), 2.60 (q, J=7.6 Hz, 2H), 1.27 (s, 9H), 1.13(t, J=7.6 Hz, 3H).

Example 281

Synthesis of ethyl2-(6-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetate(281B)

Compound 281B was prepared according to the method presented in thesynthesis of Example 272B utilizing ethyl2-(3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetateto afford the title compound; MS (m/z) 277.06 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(6-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(281C)

Compound 281C was prepared (12 mg) according to the method presented inthe synthesis of Example 54 utilizing Compound 54B and ethyl2-(6-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetateto provide the title compound; MS (m/z) 602.49 [M+H]⁺. ¹H NMR (400 MHz,cd₃od) δ 8.73 (dd, J=4.9, 1.6 Hz, 1H), 7.67 (dd, J=7.8, 1.6 Hz, 1H),7.48 (dd, J=7.8, 4.9 Hz, 1H), 7.38 (d, J=6.8 Hz, 1H), 7.31 (s, 1H), 7.20(dd, J=10.7, 8.5 Hz, 1H), 6.73-6.57 (m, 1H), 6.30 (d, J=6.1 Hz, 2H),5.36 (t, J=7.6 Hz, 1H), 5.12-4.98 (m, 2H), 3.08 (d, J=7.6 Hz, 2H), 3.03(dd, J=6.3, 3.4 Hz, 2H), 2.99-2.89 (m, 2H).

Example 282

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(2-oxo-1,2-dihydropyridin-4-yloxy)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(282)

(S)-5-(2-(1-(2-(2-chloropyridin-4-yloxy)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(332, 25 mg) was dissolved in 1 mL of acetic acid and heated up to 150°C. in a Biotage® Initiator Microwave Synthesizer for 75 min. It wascooled down and the solvent was removed. The residue was purified byreverse phase HPLC eluting with acetonitrile/water (with 0.1% TFA) toafford 5 mg of the title compound. MS (m/z) 523.27 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.61 (dd, J=4.8, 1.6 Hz, 1H), 7.56 (dd, J=7.8, 1.6 Hz,1H), 7.46-7.29 (m, 3H), 7.26 (s, 1H), 7.17 (dd, J=10.7, 8.6 Hz, 1H),6.59 (t, J=9.2 Hz, 1H), 6.23 (dd, J=9.5, 4.5 Hz, 3H), 5.85 (d, J=2.4 Hz,1H), 5.34 (t, J=7.5 Hz, 1H), 4.52 (s, 2H), 2.96 (t, J=21.2 Hz, 2H).

Example 283

Synthesis of ethyl2-(3-(trifluoromethyl)-4,5-dihydro-1H-spiro[cyclopenta[c]pyrazole-6,2′-[1,3]dithiolane]-1-yl)acetate(283A)

To a solution of ethyl2-(6-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetate (281B, 219 mg, 0.79 mmol) in CH₂C₂ (2 mL) was added1,2-ethanedithiol (100 μL, 1.2 mmol) and BF₃.2AcOH (165 μL, 1.2 mmol)under N₂. The mixture was stirred at ambient temperature for 16 hours.The reaction was quenched with saturated NaHCO₃ aqueous solution at 0°C.; and then extracted with EtOAc. The organic layer was separated,dried over MgSO₄, filtered and concentrated. The residue was purified bysilica gel chromatography eluting with EtOAc/Hexanes to afford 253 mg ofthe title compound: MS (m/z) 353.17 [M+H]⁺.

Synthesis of ethyl2-(6,6-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetate(283B)

In a Teflon vessel was added 1,3-dibromo-5,5-dimethylhydantoin (114 mg,0.4 mmol) and CH₂Cl₂ (1 mL). The mixture was allowed to stir under N₂and cooled down to −78° C. To it was added 1 mL of hydrogen fluoridepyridine (pyridine ˜30%, hydrogen fluoride ˜70%) followed by dropwiseaddition of a solution of ethyl2-(3-(trifluoromethyl)-4,5-dihydro-1H-spiro[cyclopenta[c]pyrazole-6,2′-[1,3]dithiolane]-1-yl)acetate(141 mg, 0.4 mmol) in CH₂Cl₂ (1 mL). The reaction was kept at −78° C.for 30 min, and then warmed up to −30° C. The reaction was carefullypoured to cold (0° C.) saturated NaHCO₃, and added more NaHCO₃ if pH wasless than 7. Then it was extracted with CH₂Cl₂. The organic layer wasseparated, dried over MgSO₄, filtered and concentrated. The residue waspurified by silica gel chromatography eluting with EtOAc/Hexanes toafford 40 mg of the title compound: MS (m/z) 298.97, [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(6,6-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(283C)

Compound 283C was prepared (30 mg) according to the method presented inthe synthesis of Example 54 utilizing Compound 54B and ethyl2-(6,6-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetate to provide the title compound; MS (m/z) 624.48 [M+H]⁺.¹H NMR (400 MHz, cd₃od) δ 8.72 (dd, J=4.9, 1.6 Hz, 1H), 7.68 (dd, J=7.8,1.6 Hz, 1H), 7.48 (dd, J=7.8, 4.9 Hz, 1H), 7.38 (d, J=6.9 Hz, 1H), 7.32(s, 1H), 7.21 (dd, J=10.7, 8.5 Hz, 1H), 6.76-6.57 (m, 1H), 6.30 (d,J=6.2 Hz, 2H), 5.36 (t, J=7.6 Hz, 1H), 4.96 (d, J=16.8 Hz, 2H),3.17-2.90 (m, 4H), 2.83 (dd, J=7.5, 4.4 Hz, 2H).

Example 284

Synthesis of(R)—N-(1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(284)

Compound 284 was prepared (21 mg) according to the method presented forthe synthesis of Example 279G substituting2-(5-hydroxy-1H-indol-3-yl)acetic acid for2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid to afford the titlecompound: MS (m/z) 518.8 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.10 (s, 1H),8.48 (s, 1H), 7.39 (d, J=8.3 Hz, 2H), 7.15 (dd, J=17.6, 8.5 Hz, 3H),7.06 (s, 1H), 6.83 (d, J=2.1 Hz, 1H), 6.68 (dd, J=12.7, 5.8 Hz, 2H),6.30 (d, J=6.5 Hz, 2H), 5.40 (t, J=7.5 Hz, 1H), 3.71-3.50 (m, 2H),3.06-2.84 (m, 2H).

Example 285

Synthesis of 2-ethoxycyclohex-2-enone (285A)

5 gram of cyclohexane-1,2-dione was dissolved in a mixture of 100 mL oftoluene and 50 mL of ethanol. To it was added 1 gram ofp-Toluenesulfonic acid and the solution was heated at reflux for oneday; then cooled down and removed the solvent. The residue was dissolvedin CH₂Cl₂ and washed with NaHCO₃ (sat'd aqueous solution) and halfbrine. The organic layer was separated, dried over MgSO₄, filtered andconcentrated. The residue was purified by silica gel chromatographyeluting with EtOAc/Hexanes to afford 4.6 gram of the title compound. MS(m/z) 141.08 [M+H]⁺.

Synthesis of 6-(2,2-difluoroacetyl)-2-ethoxycyclohex-2-enone (285B)

Compound 285B was prepared according to the method presented in thesynthesis of Example 60B utilizing 2-ethoxycyclohex-2-enone to providethe title compound. MS (m/z) 219.12 [M+H]⁺.

Synthesis of ethyl2-(3-(difluoromethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(285C)

Compound 285C was prepared according to the method presented in thesynthesis of Example 60C utilizing6-(2,2-difluoroacetyl)-2-ethoxycyclohex-2-enone to provide the titlecompound. MS (m/z) 273.11 [M+H]⁺.

Synthesis of ethyl2-(3′-(difluoromethyl)-5′,6′-dihydrospiro[[1,3]dithiolane-2,7′-indazole]-1′(4′H)-yl)acetate(285D)

Compound 285D was prepared according to the method presented in thesynthesis of Example 283A utilizing ethyl2-(3-(difluoromethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetateto provide the title compound. MS (m/z) 349.28 [M+H]⁺.

Synthesis of ethyl2-(3-(difluoromethyl)-7,7-difluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(285E)

Compound 285E was prepared according to the method presented in thesynthesis of Example 283B utilizing ethyl2-(3′-(difluoromethyl)-5′,6′-dihydrospiro[[1,3]dithiolane-2,7′-indazole]-1′(4′H)-yl)acetateto provide the title compound. MS (m/z) 295.02 [M+H]⁺.

Synthesis of ethyl2-(3-(difluoromethyl)-7,7-difluoro-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(285F)

Compound 285F was prepared according to the method presented in thesynthesis of Example 272A utilizing ethyl2-(3-(difluoromethyl)-7,7-difluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetateto provide the title compound. MS (m/z) 309.01 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(3-(difluoromethyl)-7,7-difluoro-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(285G)

Compound 285G was prepared (6 mg) according to the method presented inthe synthesis of Example 54 utilizing Compound 54B and ethyl2-(3-(difluoromethyl)-7,7-difluoro-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid to provide the title compound; MS (m/z) 634.43 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.72 (dd, J=4.9, 1.6 Hz, 1H), 7.63 (dd, J=7.8, 1.6 Hz,1H), 7.44 (dd, J=7.8, 4.9 Hz, 1H), 7.39 (d, J=7.0 Hz, 1H), 7.29 (s, 1H),7.20 (t, J=5.3 Hz, 1H), 6.99 (t, J=53.5 Hz, 1H), 6.66 (t, J=9.2 Hz, 1H),6.32 (d, J=6.2 Hz, 2H), 5.36 (t, J=7.5 Hz, 1H), 5.12 (s, 2H), 3.17-3.00(m, 2H), 2.85-2.56 (m, 4H).

Example 286

Synthesis of(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-1-yl)acetamide(286)

Compound 286 was prepared (8 mg) according to the method presented inthe synthesis of Example 57 utilizing Compound 55D and2-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-1-yl)acetic acid to afford thetitle compound. MS (m/z) 475.1 [M+H]⁺. ¹H NMR (400 MHz, cdcl₃) δ 8.72(s, 1H), 8.52 (s, 1H), 8.11 (m, 1H), 7.98 (d, J=8.0 Hz, 1H), 6.73-6.54(m, 3H), 5.78 (d, J=5.5 Hz, 1H), 4.78 (d, J=22.5 Hz, 2H), 3.18 (dd,J=13.6, 5.2 Hz, 1H), 3.00 (dd, J=13.5, 8.2 Hz, 1H), 2.66 (s, 2H), 2.42(s, 2H), 1.84 (s, 4H).

Example 287

Synthesis of ethyl2-(3′-(difluoromethyl)-7′,7′-difluoro-6′,7′-dihydrospiro[[1,3]dithiolane-2,4′-indazole]-1′(5′H)-yl)acetate(287A)

Compound 287A was prepared according to the method presented in thesynthesis of Example 283A utilizing ethyl2-(3-(difluoromethyl)-7,7-difluoro-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate.MS (m/z) 385.26 [M+H]⁺.

Synthesis of ethyl2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(287B)

Compound 287B was prepared according to the method presented in thesynthesis of Example 283B utilizing ethyl2-(3′-(difluoromethyl)-7′,7′-difluoro-6′,7′-dihydrospiro[[1,3]dithiolane-2,4′-indazole]-1′(5′H)-yl)acetateand substituting 2 mol equivalent of N-iodosuccinimide for1,3-dibromo-5,5-dimethylhydantoin to afford the title compound. MS (m/z)330.98 [M+H]⁺.

Synthesis of2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid (287C)

Compound 287C was prepared according to the method presented in thesynthesis of Example 60G utilizing ethyl2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetateto afford the title compound. MS (m/z) 303.08 [M+H]⁺.

Synthesis of(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(287D)

Compound 287D was prepared according to the method presented in thesynthesis of Example 55E utilizing Compound 55D and2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid to afford the title compound. MS (m/z) 597.88 [M+H]⁺.

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(6′-(methylamino)-3,3′-bipyridin-2-yl)ethyl)acetamide(287E)

Compound 287E was prepared (9 mg) according to the method presented inthe synthesis of Example 61D substitutingN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-aminefor5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridineto provide the title compound. MS (m/z) 625.22 [M+H]⁺. ¹H NMR (400 MHz,cd₃od) δ 8.74 (dd, J=4.7, 1.6 Hz, 1H), 7.64-7.53 (m, 2H), 7.47 (s, 1H),7.39 (dd, J=7.8, 4.8 Hz, 1H), 6.98 (d, J=9.2 Hz, 1H), 6.92-6.62 (m, 2H),6.42 (d, J=6.3 Hz, 2H), 5.28 (t, J=7.6 Hz, 1H), 5.13-4.96 (m, 2H), 3.13(d, J=7.7 Hz, 2H), 3.02 (s, 3H), 2.50 (d, J=12.1 Hz, 4H).

Example 288

Synthesis of(S)—N-(1-(5-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(288)

Compound 288 was prepared (35 mg) according to the method presented inthe synthesis of Example 13 utilizing Compound 172C and2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid to provide the title compound. MS (m/z) 636.29 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 9.28 (s, 1H), 9.16 (d, J=7.8 Hz, 1H), 8.62 (s, 1H), 8.10(s, 1H), 7.98 (s, 1H), 7.60 (d, J=3.5 Hz, 1H), 6.99-6.57 (m, 3H), 6.35(d, J=6.1 Hz, 2H), 5.47-5.25 (m, 1H), 5.06 (s, 2H), 3.12 (t, J=10.7 Hz,2H), 2.65-2.34 (m, 4H).

Example 289

Synthesis of (S)-ethyl1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate(289)

Compound 289 was prepared (10 mg) according to the method presented inthe synthesis of Example 56B utilizing Compound 56A and ethyl3-(trifluoromethyl)-1H-pyrazole-4-carboxylate to provide the titlecompound. MS (m/z) 620.21 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.68 (dd,J=4.8, 1.6 Hz, 1H), 8.28 (s, 1H), 7.55 (dd, J=7.8, 1.6 Hz, 1H),7.45-7.34 (m, 2H), 7.31 (s, 1H), 7.20 (dd, J=10.8, 8.5 Hz, 1H), 6.64 (m,1H), 6.29 (d, J=6.2 Hz, 2H), 5.33 (dd, J=8.6, 6.5 Hz, 1H), 4.97 (s, 2H),4.28 (q, J=7.1 Hz, 2H), 3.06 (qd, J=12.9, 7.6 Hz, 2H), 1.32 (t, J=7.1Hz, 3H).

Example 290

Synthesisof(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-ethyl-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(290)

Compound 290 was prepared (4 mg) according to the method presented inthe synthesis of Example 276 substituting(S)-5-(2-(1-(2-(4-bromo-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(58) and phenylboronic acid for(S)-5-(2-(1-(2-(4-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamideand cyclopropane boronic acid to provide the title compound. MS (m/z)652.43 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd, J=4.9, 1.6 Hz, 1H),7.64 (dd, J=7.8, 1.6 Hz, 1H), 7.56-7.34 (m, 6H), 7.28-7.16 (m, 3H), 6.67(t, J=9.3 Hz, 1H), 6.35 (d, J=6.2 Hz, 2H), 5.39 (t, J 7.5 Hz, 1H), 4.95(s, 2H), 3.08 (d, J=7.5 Hz, 2H), 2.50 (dt, J=10.4, 7.6 Hz, 2H), 0.94 (t,J=7.6 Hz, 3H).

Example 291

Synthesis of(S)-5-(2-(1-(2-(4-cyclopropyl-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(291)

Compound 291 was prepared (25 mg) according to the method presented forthe synthesis of Example 276 substituting(S)-5-(2-(1-(2-(4-bromo-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(275) for(S)-5-(2-(1-(2-(4-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamideto provide the title compound: MS (m/z) 602.32 [M+H]⁺. ¹H NMR (400 MHz,cd₃od) δ 8.70 (dd, J=4.9, 1.6 Hz, 1H), 7.68 (dd, J=7.8, 1.6 Hz, 1H),7.56-7.42 (m, 2H), 7.35 (s, 1H), 7.22 (dd, J=10.7, 8.5 Hz, 1H),6.79-6.60 (m, 1H), 6.33 (d, J=6.2 Hz, 2H), 5.36 (t, J=7.6 Hz, 1H), 4.83(s, 2H), 3.05 (d, J=7.6 Hz, 2H), 2.16 (s, 3H), 1.53 (m, 1H), 0.93-0.73(m, 2H), 0.51 (q, J=5.7 Hz, 2H).

Example 292

(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(292)

Compound 292 was prepared (10 mg) according to the method presented forthe synthesis of Example 333 to afford the title compound as a sideproduct. MS (m/z) 578.20 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd,J=4.9, 1.6 Hz, 1H), 7.71 (s, 1H), 7.63 (dd, J=7.8, 1.7 Hz, 1H),7.47-7.38 (m, 2H), 7.30 (s, 1H), 7.21 (dd, J=10.7, 8.5 Hz, 1H),6.73-6.55 (m, 1H), 6.30 (d, J=6.2 Hz, 2H), 5.35 (dd, J=13.2, 6.4 Hz,1H), 4.92 (s, 2H), 4.55 (s, 2H), 3.15-2.94 (m, 2H).

Example 293

Synthesis of(R)—N-(1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(293)

Compound 293 was prepared (24 mg) according to the method presented forthe synthesis of Example 279G substituting2-(5-fluoro-1H-indol-3-yl)acetic acid for2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid to afford the titlecompound: MS (m/z) 521.2 [M+H]⁺. ¹H NMR (400 MHz, cdcl₃) δ 9.04 (s, 1H),8.55 (s, 1H), 8.24 (s, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.35 (dd, J=8.6, 4.2Hz, 1H), 7.19 (s, 1H), 7.12 (d, J=8.2 Hz, 2H), 7.01 (t, J=9.2 Hz, 2H),6.82 (d, J=7.9 Hz, 1H), 6.56 (t, J=8.8 Hz, 1H), 6.07 (d, J=5.9 Hz, 2H),5.52 (q, J=7.5 Hz, 1H), 3.81-3.61 (m, 2H), 2.83-2.65 (m, 2H).

Example 294

Synthesis of(S)-2-(2-(3,5-difluorophenyl)-1-(2-(5-fluoro-1H-indol-3-yl)acetamido)ethyl)-3,4′-bipyridine-2′-carboxamide(294)

(S)—N-(1-(2′-cyano-3,4′-bipyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(377, 10 mg) was dissolved in 1 mL of THF and cooled down to 0° C. withice-water bath. To it was added 0.05 mL of KOH solution (50% in H₂O) and0.1 mL of hydrogen peroxide solution [30% (w/w) in water]. The reactionwas allowed to warm to ambient temperature and stirred for 16 hours andthen concentrated. The residue was purified by reverse phase HPLCeluting with acetonitrile/water (with 0.1% TFA) to afford 5.9 mg of thetitle compound. MS (m/z) 529.9 [M+H]⁺. ¹H NMR (400 MHz, cdcl₃) δ 8.68(d, J=5.0 Hz, 1H), 8.52 (d, J=4.5 Hz, 1H), 8.19-8.09 (m, 2H), 7.97 (s,1H), 7.86 (s, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.67-7.50 (m, 2H), 7.26-7.20(m, 1H), 7.13 (s, 1H), 6.92-6.75 (m, 2H), 6.51 (m, 2H), 6.03 (d, J=5.8Hz, 2H), 5.28 (dd, J=15.9, 7.6 Hz, 1H), 3.74-3.49 (m, 2H), 2.97 (dd,J=13.6, 7.2 Hz, 1H), 2.87-2.78 (m, 1H).

Example 295

Synthesis of(S)-1-(5-bromopyrimidin-4-yl)-2-(3,5-difluorophenyl)ethanaminehydrochloride (295A)

Compound 295A was prepared according to the method presented for thesynthesis of Example 279F substituting Compound 279D for Compound 279Eto afford the title compound: MS (m/z) 316.2 [M+H]⁺.

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(5-(3-sulfamoylphenyl)pyrimidin-4-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(295B)

Compound 295B was prepared (19 mg) according to the method presented inthe synthesis of Example 57 utilizing Compound 295A and2-(5-hydroxy-1H-indol-3-yl)acetic acid, then Suzuki coupling with3-sulfamoylphenylboronic acid to afford the title compound. MS (m/z)564.2 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.05 (s, 1H), 8.45 (s, 1H), 7.87(d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.27 (d, J=7.6Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 6.96 (s, 1H), 6.73 (s, 1H), 6.57 (d,J=8.6 Hz, 2H), 6.23 (d, J=6.8 Hz, 2H), 5.29 (t, J=7.5 Hz, 1H), 3.66-3.40(m, 2H), 2.90 (d, J=7.5 Hz, 2H).

Example 296

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(296)

Compound 296 was prepared (4 mg) according to the method presented inthe synthesis of Example 56B utilizing compound 56A and3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde to provide the titlecompound. MS (m/z) 620.21 [M+H]⁺. ¹H NMR (400 MHz, cdcl₃) δ 9.97 (s,1H), 8.59 (d, J=3.3 Hz, 1H), 8.14 (s, 1H), 7.64 (d, J=7.0 Hz, 1H), 7.52(d, J=7.9 Hz, 1H), 7.48-7.37 (m, 1H), 7.33 (m, 1H), 7.22-7.09 (m, 2H),6.73 (m, 1H), 6.56 (d, J=9.1 Hz, 1H), 6.12 (d, J=6.6 Hz, 2H), 5.87 (s,1H), 5.44 (d, J=6.3 Hz, 1H), 4.89 (s, 2H), 2.93 (s, 2H).

Example 297

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4-vinyl-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(297)

(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-ethynyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(341, 40 mg) was dissolved in 10 mL of EtOAc. The system was purged withargon and then 30 mg of Lindlar Catalyst was added. The reaction wasstirred for 20 hours under 1 atm H₂ at ambient temperature. Uponcompletion of the reaction, it was filtered through a pad of celite andwashed with EtOAc. The filtrate was collected and the volatiles wereremoved in vacuo. The residue was purified by reverse phase HPLC elutingwith acetonitrile/water (with 0.1% TFA) to afford 15 mg of the titlecompound. MS (m/z) 574.40 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.69 (dd,J=4.9, 1.6 Hz, 1H), 7.93 (s, 1H), 7.64 (dd, J=7.8, 1.6 Hz, 1H),7.49-7.40 (m, 2H), 7.33 (s, 1H), 7.21 (dd, J=10.7, 8.6 Hz, 1H), 6.65 (t,J=9.2 Hz, 1H), 6.60-6.48 (m, 1H), 6.30 (d, J=6.2 Hz, 2H), 5.58 (d,J=17.7 Hz, 1H), 5.35 (t, J=7.5 Hz, 1H), 5.22 (dd, J=11.2, 1.2 Hz, 1H),4.91 (s, 2H), 3.06 (d, J=7.8 Hz, 2H).

Example 298

Synthesis of 2-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid(298A)

6-methoxy-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.69 mmol) was dissolved in2 mL of DMF and cooled down to 0° C. To it was added NaH (60% in oildispersion, 68 mg, 1.69 mmol) portionwise. The mixture was stirred atambient temperature for 20 min, a solution of methyl 2-bromoacetate (192μL, 2 mmol) in 0.5 mL of DMF was added dropwise. It was stirred for 2hours and quenched with saturated aqueous NH₄Cl solution. The mixturewas partitioned between EtOAc and water. The organic layer wasseparated, dried over MgSO₄, filtered and concentrated to afford crudemethyl 2-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-1-yl)acetate which wasdissolved in 5 mL of THF/MeOH/H₂O (3/2/1) and to it was added LiOH.H₂O(355 mg, 8.45 mmol). The mixture was stirred at ambient temperature for20 min and concentrated to small volume. It was filtered and purified byreverse phase HPLC eluting with acetonitrile/water (with 0.1% TFA) toafford 186 mg of the title compound. MS (m/z) 205.1 [M−H]⁻

Synthesis of 2-(6-oxo-6,7-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)aceticacid (298B)

2-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid (100 mg, 0.48mmol) was dissolved in 5 mL of acetonitrile. To it was added KI (161 mg,0.96 mmol) and TMSCl (122 μL, 0.96 mmol) The reaction mixture was heatedup to 80° C. for 4 hours and cooled down to ambient temperature. It wasfiltered and purified by reverse phase HPLC eluting withacetonitrile/water (with 0.1% TFA) to afford 30 mg of the titlecompound. MS (m/z) 193.3 [M+H]⁺.

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(6-oxo-6,7-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(298C)

Compound 298C was prepared (6 mg) according to the method presented inthe synthesis of Example 50D utilizing compound 50C and2-(6-oxo-6,7-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid toprovide the title compound. MS (m/z) 528.0 [M+H]⁺. ¹H NMR (400 MHz,cd₃od) δ 8.69 (d, J=4.9 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.89 (d, J=7.8Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.64 (s, 1H), 7.48 (dd, J=10.2, 5.0 Hz,2H), 7.28 (d, J=7.1 Hz, 1H), 7.03 (d, J=3.5 Hz, 1H), 6.64 (t, J=9.2 Hz,1H), 6.51 (d, J=8.5 Hz, 1H), 6.46 (d, J=3.5 Hz, 1H), 6.23 (d, J=6.2 Hz,2H), 5.42 (t, J=7.5 Hz, 1H), 4.93 (s, 2H), 3.10-2.96 (m, 2H).

Example 299

Synthesis of bicyclo[4.1.0]heptan-2-one (299A)

Compound 299A was prepared according to the method presented inTetrahedron, Vol. 51. No. 43, p. 11757, 1995.

¹H NMR (400 MHz, cdcl3) δ 2.27-2.18 (m, 1H), 2.05-1.79 (m, 4H),1.72-1.47 (m, 3H), 1.14 (m, 1H), 1.08-0.92 (m, 1H).

Synthesis of ethyl2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetate(299B)

Compound 299B was prepared according to the method presented in thesynthesis of Example 60C utilizing bicyclo[4.1.0]heptan-2-one to providethe title compound as a mixture of diastereomers. MS (m/z) 271.17[M+H]⁺.

Synthesis of2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)aceticacid (299C)

Ethyl2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetate(27 mg, 0.1 mmol) was dissolved in 2 mL of THF/MeOH/H₂O (3/2/1) and toit was added LiOH.H₂O (13 mg, 0.3 mmol). The mixture was stirred atambient temperature for 10 min and cooled down to 0° C. It was acidifiedwith 1N HCl and extracted with EtOAc. The organic layer was separated,dried over MgSO₄, filtered and concentrated to afford the titlecompound. MS (m/z) 243.12 [M+H]⁺.

Synthesis ofN-(1-(5-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetamide(299D)

Compound 299D was prepared (30 mg) according to the method presented inthe synthesis of Example 13 utilizing Compound 172C and2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetic acid to provide the title compound as mixture ofdiastereomers. MS (m/z) 576.38 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.20(d, J=2.1 Hz, 1H), 8.60 (s, 1H), 7.95 (s, 1H), 7.81 (d, J=1.9 Hz, 1H),7.46 (d, J=3.5 Hz, 1H), 6.76-6.66 (m, 1H), 6.60-6.41 (m, 2H), 6.31 (t,J=5.7 Hz, 2H), 5.48 (td, J=7.5, 3.3 Hz, 1H), 4.87 (s, 2H), 3.12-2.94 (m,2H), 2.70 (dd, J=15.7, 5.7 Hz, 1H), 2.11 (ddt, J=41.1, 27.6, 14.0 Hz,2H), 1.88-1.69 (m, 2H), 1.60 (m, 1H), 0.94 (dtd, J=13.2, 8.2, 4.9 Hz,1H), 0.65 (m, 1H).

Example 300

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-((dimethylamino)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(300)

Compound 300 was prepared (8 mg) according to the method presented forthe synthesis of Example 333 substituting dimethylamine hydrochloridefor methylamine hydrochloride to afford the title compound: MS (m/z)605.29 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd, J=4.8, 1.6 Hz, 1H),8.02 (s, 1H), 7.59 (dd, J=7.8, 1.6 Hz, 1H), 7.49 (d, J=5.0 Hz, 1H), 7.41(dd, J=7.8, 4.8 Hz, 1H), 7.31-7.14 (m, 2H), 6.66 (m, 1H), 6.33 (d, J=6.2Hz, 2H), 5.41-5.26 (m, 1H), 5.02 (s, 2H), 4.31 (s, 2H), 3.09 (qd,J=13.0, 7.6 Hz, 2H), 2.86 (s, 6H).

Example 301

Synthesis of1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethanimine(301A)

5-(4-chlorophenyl)pyrimidine-4-carbonitrile (215 mg, 1 mmol) wasdissolved in toluene and cooled down to 0° C. To it was added(3,5-difluorobenzyl)magnesium bromide (0.25 M in ether, 4.8 ml, 1.2mmol) dropwise. After stirring for 30 min the reaction was allowed towarm to ambient temperature and stirred for 1 hour. It was cooled downto 0° C. again and 3 mL of 2-butanol was added followed by NaBH₄ (76 mg,2 mmol) and the reaction was stirred at ambient temperature for 16hours. The reaction was quenched with water at 0° C. and extracted withEtOAc. The organic layer was separated, dried over MgSO₄, filtered andconcentrated. The residue was purified by silica gel chromatographyeluting with EtOAc/Hexanes to afford 100 mg of the title compound. MS(m/z) 344.2 [M+H]⁺.

Synthesis of(S)—N-(1-(5-(4-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(301B)

2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid(25 mg, 0.1 mmol) and1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethanimine(35 mg, 0.1 mmol) was dissolved in 1 mL of DMF and cooled down to 0° C.To it was added N,N-Diisopropylethylamine (52 μL, 0.3 mmol) followed byHATU (46 mg, 0.12 mmol). The reaction was allowed to stir at 0° C. for20 min and then purified by reverse phase HPLC eluting withacetonitrile/water (with 0.1% TFA). The fractions were combined andheated up to 60° C. for 20 min. After cooled down to room temperature itwas purified by reverse phase HPLC again eluting with acetonitrile/water(with 0.1% TFA) to afford 5 mg of the title compound. MS (m/z) 592.1[M+H]⁺. ¹H NMR (400 MHz, cdcl₃) δ 9.54 (s, 1H), 8.41 (s, 1H), 7.49-7.34(m, 3H), 7.11 (t, J=8.8 Hz, 2H), 6.68 (t, J=8.8 Hz, 1H), 6.44 (d, J=5.6Hz, 2H), 4.99 (m, 1H), 4.68 (q, J=16.8 Hz, 2H), 2.79-2.50 (m, 4H),2.47-2.23 (m, 2H), 1.97-1.70 (m, 4H).

Example 302

Synthesis of(S)—N-(1-(2′-(2H-tetrazol-5-yl)-3,4′-bipyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(302)

(S)—N-(1-(2′-cyano-3,4′-bipyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(377, 8 mg, 0.016 mmol) was dissolved in 1 mL of isopropanol and 1 mL ofwater. To it was added zinc bromide (3.5 mg, 0.016 mmol) and sodiumazide (3 mg, 0.048 mmol). The reaction mixture was heated up to 100° C.for 16 hours. It was cooled down and filtered. The residue was purifiedby reverse phase HPLC twice eluting with acetonitrile/water (with 0.1%TFA) to afford 3.5 mg of the title compound. MS (m/z) 555.2 [M+H]⁺. ¹HNMR (400 MHz, cd₃od) δ 8.61 (d, J=4.4 Hz, 2H), 7.62 (s, 1H), 7.55 (d,J=6.2 Hz, 1H), 7.41-7.28 (m, 2H), 7.19 (dd, J=8.8, 4.4 Hz, 1H), 7.09 (s,1H), 7.01 (d, J=2.3 Hz, 1H), 6.79-6.69 (m, 1H), 6.43 (t, J=9.2 Hz, 1H),6.18 (d, J=6.2 Hz, 2H), 5.27 (t, J=7.6 Hz, 1H), 3.54 (s, 2H), 2.94 (d,J=7.6 Hz, 2H).

Example 303

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(303)

(S)-tert-butyl1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-3-(trifluoromethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(274, 269 mg, 0.38 mmol) was dissolved in 3 mL of 1,4-dioxane and to itwas added 1 mL of HCl solution (4 N in 1,4-dioxane). The mixture wasallowed to stir at ambient temperature for 1 day. To it was addeddiethyl ether and the resulting precipitate was collected by vacuumfiltration and further high vacuum drying to afford 210 mg of the titlecompound. MS (m/z) 603.30 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.82 (dd,J=5.4, 1.5 Hz, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.77 (dd, J=7.9, 5.4 Hz,1H), 7.67 (m, 1H), 7.32 (s, 1H), 7.28-7.19 (m, 1H), 6.73 (t, J=9.2 Hz,1H), 6.38 (d, J=6.2 Hz, 2H), 5.41 (dd, J=9.0, 6.5 Hz, 1H), 5.11-4.94 (m,2H), 3.59-3.49 (m, 2H), 3.23 (dd, J=13.3, 6.5 Hz, 1H), 3.12-3.06 (m,1H), 3.02 (d, J=5.8 Hz, 2H).

Example 304

Synthesis of ethyl2-(3-(difluoromethyl)-4-oxo-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetate (304A)

Compound 304A was prepared according to the method presented in thesynthesis of Example 272A substituting Compound 299B for ethyl2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate toafford the title compound; MS (m/z) 303.16 [M+H]⁺.

Synthesis of ethyl2-(3-(difluoromethyl)-4,4-difluoro-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetate(304B)

Compound 304B was prepared according to the method presented in thesynthesis of Example 285E substituting Compound 304A for Compound 285Cto afford the title compound. MS (m/z) 307.19 [M+H]⁺.

Synthesis of 5-(2-((1S)-1-(2-(3-(difluoromethyl)-4,4-difluoro-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(304C)

Compound 304C was prepared according to the method presented in thesynthesis of Example 54 utilizing Compound 54B and2-(4,4-difluoro-3-(trifluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)aceticacid to provide 6 mg of the title compound. MS (m/z) 632.09 [M+H]⁺. ¹HNMR (400 MHz, cd₃od) δ 8.69 (t, J=3.3 Hz, 1H), 7.68-7.55 (m, 1H),7.51-7.40 (m, 2H), 7.31 (m, 1H), 7.22 (t, J=9.6 Hz, 1H), 6.90-6.45 (m,2H), 6.34 (dd, J=13.1, 6.4 Hz, 2H), 5.36 (q, J=7.6 Hz, 1H), 5.06-4.91(m, 2H), 3.17-2.92 (m, 2H), 2.62 (t, J=16.4 Hz, 1H), 2.39-2.17 (m, 1H),2.04 (m, 1H), 1.77 (m, 1H), 1.17 (dd, J=14.2, 5.7 Hz, 1H), 0.46 (m, 1H).

Example 305

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-(morpholinomethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(305)

Compound 305 was prepared according to the method presented for thesynthesis of Example 333 substituting morpholine for methylaminehydrochloride to afford 7 mg of the title compound: MS (m/z) 647.27[M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd, J=4.8, 1.6 Hz, 1H), 8.02 (s,1H), 7.68-7.58 (m, 1H), 7.52 (d, J=6.8 Hz, 1H), 7.41 (dd, J=7.8, 4.8 Hz,1H), 7.30-7.10 (m, 2H), 6.66 (dd, J=10.4, 8.1 Hz, 1H), 6.34 (d, J=6.2Hz, 2H), 5.38-5.28 (m, 1H), 5.02 (s, 2H), 4.35 (s, 2H), 4.04 (bs, 2H),3.73 (bs, 2H), 3.40 (bs, 2H), 3.09 (m, 4H).

Example 306

Synthesis of 2-(6-methoxy-3-methyl-1H-indazol-1-yl)acetic acid (306A)

Compound 306A was prepared according to the method presented for thesynthesis of Example 298A substituting 6-methoxy-3-methyl-1H-indazolefor 6-methoxy-1H-pyrrolo[2,3-b]pyridine to afford the title compound: MS(m/z) 221.3 [M+H]⁺.

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(6-methoxy-3-methyl-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(306B)

Compound 306B was prepared according to the method presented in thesynthesis of Example 50D utilizing Compound 50C and2-(6-methoxy-3-methyl-1H-indazol-1-yl)acetic acid to provide the titlecompound. MS (m/z) 556.2 [M+H]⁺.

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(6-hydroxy-3-methyl-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(306C)

(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(6-methoxy-3-methyl-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(21 mg, 0.038 mmol) was dissolved in 1 mL of CH₂Cl₂ and cooled down to−78 OC with dry ice-acetone bath. To it was added BBr₃ (1 M in CH₂Cl₂)and the reaction mixture was allowed to warm to ambient temperature andstirred for 16 hours. It was quenched with NaHCO₃ (sat'd aqueoussolution) and extracted with EtOAc. The organic layer was separated,washed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by reverse phase HPLC eluting withacetonitrile/water (with 0.1% TFA) to afford 9.3 mg of the titlecompound. MS (m/z) 542.0 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.56 (d,J=4.9 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.49 (s,1H), 7.46-7.32 (m, 3H), 7.16 (d, J=7.2 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H),6.56 (d, J=10.1 Hz, 2H), 6.12 (d, J=6.5 Hz, 2H), 5.35 (t, J=7.5 Hz, 1H),4.83 (s, 2H), 2.88 (d, J=7.6 Hz, 2H), 2.39 (s, 3H).

Example 307

Synthesis of(S)-5-(2-(1-(2-(3-(difluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(307)

Compound 307 was prepared according to the method presented in thesynthesis of Example 56B utilizing Compound 56A and3-(difluoromethyl)-4,5,6,7-tetrahydro-1H-indazole to provide 6 mg of thetitle compound. MS (m/z) 584.36 [M+H]⁺.

¹H NMR (400 MHz, cdcl₃) δ 9.59-9.33 (m, 3H), 8.79 (dd, J=5.5, 1.4 Hz,1H), 7.97 (dd, J=7.9, 1.5 Hz, 1H), 7.82-7.58 (m, 2H), 7.34-7.26 (m, 1H),6.99 (d, J=9.8 Hz, 1H), 6.76 (m, 1H), 6.67-6.53 (m, 1H), 6.19 (d, J=5.7Hz, 2H), 5.47 (dd, J=16.1, 7.2 Hz, 1H), 4.84-4.57 (m, 2H), 3.17 (dd,J=13.6, 7.1 Hz, 1H), 3.01 (dd, J=13.6, 9.1 Hz, 1H), 2.59 (t, J=5.6 Hz,2H), 2.42 (t, J=10.4 Hz, 2H), 1.75 (dd, J=30.7, 5.7 Hz, 4H).

Example 308

Synthesis of(S)-5-(4-(1-(2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyrimidin-5-yl)-2-fluorobenzamide(308)

Compound 308 was prepared according to the method presented in thesynthesis of Example 54G utilizing Compound 136C and2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid to provide 11 mg of the title compound. MS (m/z) 636.29 [M+H]⁺. ¹HNMR (400 MHz, cd₃od) δ 9.23 (s, 1H), 9.12 (d, J=7.9 Hz, 1H), 8.55 (s,1H), 7.46 (d, J=5.8 Hz, 2H), 7.33-7.20 (m, 1H), 6.96-6.58 (m, 2H), 6.40(d, J=6.1 Hz, 2H), 5.36 (q, J=7.7 Hz, 1H), 5.04 (s, 2H), 3.08 (d, J=7.6Hz, 2H), 2.63-2.33 (m, 4H).

Example 309

Synthesis of(S)-5-(2-(1-(2-(5,6-dichloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(309)

Compound 309 was prepared according to the method presented in thesynthesis of Example 56B utilizing Compound 56A and5,6-dichloro-1H-benzo[d]imidazol-2(3H)-one to provide 25 mg of the titlecompound. MS (m/z) 614.72 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.72 (d,J=4.7 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.53-7.30 (m, 3H), 7.27-7.14 (m,2H), 7.07 (s, 1H), 6.66 (t, J=9.2 Hz, 1H), 6.32 (d, J=6.2 Hz, 2H), 5.36(t, J=7.7 Hz, 1H), 4.64-4.44 (m, 2H), 3.07 (d, J=7.4 Hz, 2H).

Example 310

Synthesis of(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(310A)

Compound 310A was prepared according to the method presented in thesynthesis of Example 55E utilizing compound 55D and2-(5-hydroxy-1H-indol-3-yl)acetic acid to provide the title compound. MS(m/z) 486.00 [M+H]⁺.

Synthesis of(S)—N-(1-(2′-cyano-3,4′-bipyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(310B)

To a mixture of Compound 310A (49 mg, 0.1 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (35 mg,0.15 mmol) and potassium carbonate (41 mg, 0.3 mmol) was added 1 mL of1,4-dioxane. After the system was purged with argon, palladium (II)acetate (2.2 mg, 0.01 mmol) and tricyclohexylphosphine (5.6 mg, 0.02mmol) was added and the reaction mixture was heated up to 100° C. for 16hours. It was cooled down and partitioned between EtOAc and water. Theorganic layer was separated, washed with brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reverse phaseHPLC eluting with acetonitrile/water (with 0.1% TFA) to afford the titlecompound. MS (m/z) 509.8 [M+H]⁺.

Synthesis of(S)-2-(2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-1H-indol-3-yl)acetamido)ethyl)-3,4′-bipyridine-2′-carboxamide(310C)

Compound 310C was prepared according to the method presented for thesynthesis of Example 294 substituting Compound 310B for Compound 377 toafford 4 mg of the title compound: MS (m/z) 528.2 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.51 (dd, J=14.7, 4.9 Hz, 2H), 7.61-7.47 (m, 2H), 7.32(dd, J=7.9, 4.8 Hz, 2H), 7.08 (d, J=8.6 Hz, 1H), 6.98 (s, 1H), 6.73 (d,J=2.0 Hz, 1H), 6.62-6.47 (m, 2H), 6.13 (d, J=6.2 Hz, 2H), 5.30-5.11 (m,1H), 3.51 (s, 2H), 2.97-2.75 (m, 2H).

Example 311

Synthesis of ethyl2-(7,7-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(311A)

Compound 311A was prepared according to the method presented in thesynthesis of Example 285E substituting Compound 272B for Compound 285Cto afford the title compound. MS (m/z) 313.05 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(7,7-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(311B)

Compound 311B was prepared according to the method presented in thesynthesis of Example 54 utilizing Compound 54B and ethyl ethyl2-(7,7-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetateto provide 43 mg of the title compound; MS (m/z) 638.46 [M+H]⁺. ¹H NMR(400 MHz, cd₃od) δ 8.72 (dd, J=5.0, 1.6 Hz, 1H), 7.71 (dd, J=7.8, 1.6Hz, 1H), 7.51 (dd, J=7.8, 5.0 Hz, 1H), 7.44-7.27 (m, 2H), 7.22 (dd,J=10.7, 8.6 Hz, 1H), 6.66 (tt, J=9.2, 2.3 Hz, 1H), 6.31 (t, J=6.3 Hz,2H), 5.36 (t, J=7.6 Hz, 1H), 5.15-4.97 (m, 2H), 3.05 (t, J=10.6 Hz, 2H),2.65 (s, 2H), 2.32-2.16 (m, 2H), 2.06-1.85 (m, 2H).

Example 312

Synthesis of(S)-1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide(312)

To a solution of(S)-1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylicacid (323, 30 mg, 0.05 mmol) in 0.5 mL of DMF were added HOBt (10 mg,0.075 mmol), 0.5 M ammonia solution in 1,4-dioxane (0.5 mL, 0.25 mmol),N,N-diisopropylethylamine (26 μL, 0.15 mmol), and HATU (29 mg, 0.075mmol). After stirring for 2 hours at room temperature, It waspartitioned between EtOAc and saturated NaHCO₃ aqueous solution. Theorganic layer was separated, washed with brine, dried over MgSO₄,filtered and concentrated. The residue was purified by reverse phaseHPLC eluting with acetonitrile/water (with 0.1% TFA) to afford 10 mg ofthe title compound. MS (m/z) 591.34 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ8.70-8.56 (m, 1H), 8.09 (s, 1H), 7.47 (dd, J=7.8, 1.7 Hz, 1H), 7.37-7.25(m, 2H), 7.14 (m, 2H), 6.56 (t, J=9.3 Hz, 1H), 6.22 (d, J=6.3 Hz, 2H),5.36-5.18 (m, 1H), 4.88 (s, 2H), 2.99 (m, 2H).

Example 313

Synthesis of(R)-3-(4-(2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-1H-indol-3-yl)acetamido)ethyl)pyrimidin-5-yl)benzamide(313)

Compound 313 was prepared according to the method presented for thesynthesis of Example 295B substituting Compound 279F and3-carbamoylphenylboronic acid for Compound 295A and3-sulfamoylphenylboronic acid to afford 19 mg of the title compound: MS(m/z) 528.4 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.13 (s, 1H), 8.54 (s,1H), 7.94 (d, J=8.1 Hz, 1H), 7.65 (s, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.37(d, J=7.2 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.06 (s, 1H), 6.83 (s, 1H),6.65 (t, J=10.3 Hz, 2H), 6.27 (d, J=6.5 Hz, 2H), 5.45 (t, J=7.4 Hz, 1H),3.71-3.50 (m, 2H), 2.97 (d, J=7.5 Hz, 2H).

Example 314

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-((ethylamino)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(314)

Compound 314 was prepared according to the method presented for thesynthesis of Example 333 substituting ethylamine hydrochloride formethylamine hydrochloride to afford 5 mg of the title compound: MS (m/z)605.32 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd, J=4.8, 1.6 Hz, 1H),7.94 (s, 1H), 7.57 (dd, J=7.8, 1.7 Hz, 1H), 7.48 (d, J=5.0 Hz, 1H), 7.39(dd, J=7.8, 4.8 Hz, 1H), 7.30-7.12 (m, 2H), 6.66 (dd, J=10.4, 8.1 Hz,1H), 6.33 (d, J=6.2 Hz, 2H), 5.46-5.22 (m, 1H), 4.99 (s, 2H), 4.18 (s,2H), 3.16-3.00 (m, 4H), 1.31 (t, J=7.3 Hz, 3H).

Example 315

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(6-(trifluoromethoxy)-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(315)

Compound 315 was prepared according to the method presented in thesynthesis of Example 55F utilizing Compound 55D and2-(6-(trifluoromethoxy)-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)aceticacid to afford(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(6-(trifluoromethoxy)-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)acetamideand then Suzuki coupling with 3-carbamoylphenylboronic acid to provide17 mg of the title compound. MS (m/z) 663.7 [M+H]⁺. ¹H NMR (400 MHz,cd₃od) δ 8.75 (d, J=4.9 Hz, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.67 (d, J=7.8Hz, 1H), 7.55 (d, J=6.8 Hz, 2H), 7.50-7.41 (m, 2H), 7.31 (dd, J=19.6,8.3 Hz, 2H), 6.67 (t, J=9.2 Hz, 1H), 6.29 (d, J=6.3 Hz, 2H), 5.44 (t,J=7.6 Hz, 1H), 5.22 (s, 2H), 3.10-3.03 (m, 2H).

Example 316

Synthesis of(S)—N-(1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(316)

Compound 316 was prepared according to the method presented for thesynthesis of Example 279G substituting Compound 279D and2-(5-hydroxy-1H-indol-3-yl)acetic acid for Compound 279E and2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid to afford 12 mg ofthe title compound: MS (m/z) 519.3 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ9.10 (s, 1H), 8.48 (s, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.15 (dd, J=17.5,8.5 Hz, 3H), 7.06 (s, 1H), 6.83 (s, 1H), 6.67 (d, J=9.2 Hz, 2H), 6.30(d, J=6.8 Hz, 2H), 5.40 (t, J=7.6 Hz, 1H), 3.68-3.51 (m, 2H), 2.96 (d,J=7.8 Hz, 2H).

Example 317

Synthesis of(S)-5-(2-(1-(2-(5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(317)

Compound 317 was prepared according to the method presented in thesynthesis of Example 56 utilizing Compound 56A and5-cyclopropyl-3-(difluoromethyl)-1H-pyrazole to provide 36 mg of thetitle compound. MS (m/z) 570.34 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70(dd, J=4.9, 1.7 Hz, 1H), 7.79-7.65 (m, 1H), 7.57-7.46 (m, 1H), 7.34 (s,1H), 7.23 (dt, J=10.9, 4.3 Hz, 1H), 6.73-6.42 (m, 2H), 6.32 (dd, J=18.4,5.2 Hz, 2H), 6.11 (s, 1H), 5.37 (dd, J=16.3, 8.8 Hz, 1H), 4.95 (s, 2H),3.10-2.93 (m, 2H), 1.71-1.57 (m, 1H), 0.97-0.80 (m, 2H), 0.72-0.55 (m,2H).

Example 318

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(318)

Compound 318 was prepared according to the method presented for thesynthesis of Example 332 substituting 1H-benzo[d]imidazol-2(3H)-one for2-chloropyridin-4-ol to afford 10 mg of the title compound: MS (m/z)546.37 [M+H]⁺. ¹H NMR (400 MHz, cd3od) δ 8.63 (dd, J=5.0, 1.6 Hz, 1H),7.63 (dd, J=7.8, 1.6 Hz, 1H), 7.46-7.20 (m, 3H), 7.13 (dd, J=10.7, 8.5Hz, 1H), 7.02-6.87 (m, 3H), 6.77 (d, J=7.0 Hz, 1H), 6.64-6.52 (m, 1H),6.26 (d, J=6.1 Hz, 2H), 5.31 (t, J=7.6 Hz, 1H), 4.76 (s, 12H), 3.12-2.83(m, 2H).

Example 319

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5,6-dimethyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(319)

Compound 319 was prepared according to the method presented in thesynthesis of Example 54 utilizing Compound 54B and2-(5,6-dimethyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)acetic acidto provide 11 mg of the title compound. MS (m/z) 625.5 [M+H]⁺. ¹H NMR(400 MHz, cd₃od) δ 8.73 (d, J=4.7 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.52(s, 1H), 7.40 (dd, J=7.7, 4.9 Hz, 2H), 7.30 (s, 1H), 7.23 (s, 1H),7.21-7.11 (m, 1H), 6.68 (t, J=9.3 Hz, 1H), 6.35 (d, J=6.4 Hz, 2H), 5.35(t, J=7.5 Hz, 1H), 5.19-5.00 (m, 2H), 3.15-2.98 (m, 2H), 2.38 (s, 6H).

Example 320

Synthesis of(S)—N-(1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetamide(320)

Compound 320 was prepared according to the method presented for thesynthesis of Example 316 substituting2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid for2-(5-hydroxy-1H-indol-3-yl)acetic acid to afford 11 mg of the titlecompound: MS (m/z) 531.9 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.23 (d,J=13.3 Hz, 2H), 8.54 (s, 1H), 7.59 (s, 1H), 7.46-7.36 (m, 3H), 7.18 (d,J=8.0 Hz, 2H), 6.74 (t, J=9.1 Hz, 1H), 6.38 (d, J=6.8 Hz, 2H), 5.45 (d,J=7.2 Hz, 1H), 5.25 (s, 2H), 3.08 (m, 2H), 2.45 (s, 6H).

Example 321

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(4-methyl-2-oxoquinolin-1(2H)-yl)acetamido)ethyl)pyridin-3-yl)benzamide(321)

Compound 321 was prepared according to the method presented in thesynthesis of Example 55 utilizing Compound 55D and2-(4-methyl-2-oxoquinolin-1(2H)-yl)acetic acid to afford(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(4-methyl-2-oxoquinolin-1(2H)-yl)acetamide,and then Suzuki coupling with 3-carbamoylphenylboronic acid to provide18 mg of the title compound. MS (m/z) 553.0 [M+H]⁺. ¹H NMR (400 MHz,cd₃od) δ 8.83-8.68 (m, 1H), 7.87 (dd, J=12.7, 7.9 Hz, 2H), 7.80-7.69 (m,1H), 7.62 (s, 1H), 7.59-7.41 (m, 3H), 7.38-7.15 (m, 3H), 6.67 (t, J=9.3Hz, 1H), 6.60 (s, 1H), 6.30 (d, J=6.2 Hz, 2H), 5.48 (t, J=7.6 Hz, 1H),5.21-5.02 (m, 2H), 3.12-2.97 (m, 2H), 2.51 (s, 3H).

Example 322

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(6-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(322)

Compound 322 was prepared according to the method presented for thesynthesis of Example 60H substituting 3-ethoxycyclohex-2-enone forbicyclo[3.1.0]hexan-3-one to afford 8 mg of the title compound: MS (m/z)616.02 [M+H]⁺. ¹H NMR (400 MHz, cdcl₃) δ 9.99 (d, J=7.2 Hz, 1H), 8.81(d, J=5.6 Hz, 1H), 8.13-8.01 (m, 1H), 7.83 (dd, J=7.9, 5.6 Hz, 2H), 7.60(m, 1H), 7.30 (dd, J=11.2, 8.6 Hz, 1H), 6.98 (s, 2H), 6.62 (t, J=8.9 Hz,1H), 6.20 (d, J=5.6 Hz, 2H), 5.48 (dd, J=16.4, 7.2 Hz, 1H), 4.80 (q,J=16.7 Hz, 2H), 3.37 (q, J=20.3 Hz, 2H), 3.22 (dd, J=13.6, 6.8 Hz, 1H),3.07-2.86 (m, 3H), 2.66 (t, J=6.8 Hz, 2H).

Example 323

Synthesis of(S)-1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylicacid (323)

Compound 289 (352 mg, 0.57 mmol) was dissolved in 10 mL of THF/MeOH/H₂O(3/2/1) and to it was added LiOH.H₂O (119 mg, 2.8 mmol). The mixture wasstirred at ambient temperature for 16 hours. It was acidified at 0° C.with 1N HCl and extracted with EtOAc. The organic layer was separated,dried over MgSO₄, filtered and concentrated. The residue was purified byreverse phase HPLC eluting with acetonitrile/water (with 0.1% TFA) toafford 256 mg of the title compound. MS (m/z) 592.25 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.71 (dd, J=4.9, 1.6 Hz, 1H), 8.26 (s, 1H), 7.66 (dd,J=7.8, 1.6 Hz, 1H), 7.51-7.40 (m, 2H), 7.34 (s, 1H), 7.22 (dd, J=10.7,8.6 Hz, 1H), 6.65 (dd, J=10.3, 8.1 Hz, 1H), 6.31 (d, J=6.2 Hz, 2H), 5.35(t, J=7.6 Hz, 1H), 4.99 (s, 2H), 3.08 (d, J=7.6 Hz, 2H).

Example 324

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(324)

Compound 303 (30 mg, 0.05 mmol) was dissolved in 1 mL of1,2-dichloroethane. To it was added formic acid solution (40% in water,15 mg, 0.5 mmol) and acetic acid (29 μL, 0.5 mmol). After stirring atambient temperature for 20 min, NaBH(OAc)₃ (16 mg, 0.15 mmol) was added,and the reaction mixture was stirred for 10 min. The reaction wasquenched by adding NaHCO₃ (saturated aqueous solution), and extracted byEtOAc. The organic layer was separated, washed with half brine, driedover MgSO₄ and filtered. The filtrate was concentrated and purified byreverse phase HPLC eluting with acetonitrile/water (with 0.1% TFA) toafford 19.1 mg of the title compound. MS (m/z) 617.39 [M+H]⁺. ¹H NMR(400 MHz, cd₃od) δ 8.71 (dd, J=4.8, 1.6 Hz, 1H), 7.64-7.58 (m, 1H), 7.53(d, J=6.4 Hz, 1H), 7.41 (dd, J=7.8, 4.8 Hz, 1H), 7.27-7.12 (m, 2H), 6.67(t, J=9.2 Hz, 1H), 6.34 (d, J=6.2 Hz, 2H), 5.42-5.25 (m, 1H), 4.94 (s,2H), 4.29 (bs, 2H), 3.52 (bs, 2H), 3.20-2.93 (m, 7H).

Example 325

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(6-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(325)

Compound 322 (30 mg, 0.049 mmol) was dissolved in 2 mL of CH₂Cl₂ and 1mL of isopropanol. To it was added NaBH₄ (36 mg, 0.98 mmol) and theresulting mixture was stirred at ambient temperature for 4 hours. Thereaction was quenched by adding NaHCO₃ (saturated aqueous solution), andextracted by EtOAc. The organic layer was separated, washed with halfbrine, dried over MgSO₄ and filtered. The filtrate was concentrated andpurified by reverse phase HPLC eluting with acetonitrile/water (with0.1% TFA) to afford 19.1 mg of the title compound. MS (m/z) 618.51[M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.71 (dd, J=4.9, 1.6 Hz, 1H), 7.68 (m,1H), 7.47 (m, 2H), 7.32 (s, 1H), 7.26-7.07 (m, 1H), 6.79-6.58 (m, 1H),6.32 (t, J=7.1 Hz, 2H), 5.36 (q, J=7.4 Hz, 1H), 4.81 (s, 2H), 4.13 (d,J=5.7 Hz, 1H), 3.06 (d, J=7.7 Hz, 2H), 2.87-2.64 (m, 2H), 2.65-2.37 (m,2H), 1.82 (m, 2H).

Example 326

Synthesis of(S)-2-fluoro-5-(2-(2-(3-fluorophenyl)-1-(2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(326)

Compound 326 was prepared according to the method presented in thesynthesis of Example 59 utilizing Compound 59D and2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid to provide 21mg of the title compound. MS (m/z) 528.35 [M+H]⁺. ¹H NMR (400 MHz,cd₃od) δ 8.72 (dd, J=5.0, 1.5 Hz, 1H), 7.71 (dd, J=7.8, 1.6 Hz, 1H),7.52 (dd, J=7.8, 5.0 Hz, 1H), 7.32 (d, J=6.3 Hz, 2H), 7.17 (dd, J=10.6,8.7 Hz, 1H), 7.11-6.94 (m, 4H), 6.91-6.79 (m, 2H), 6.48 (dd, J=22.6, 8.5Hz, 2H), 5.40-5.31 (m, 1H), 4.56 (s, 2H), 3.17-2.95 (m, 2H).

Example 327

Synthesis of(S)-3-(4-(2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-1H-indol-3-yl)acetamido)ethyl)pyrimidin-5-yl)benzamide(327)

Compound 327 was prepared according to the method presented for thesynthesis of Example 295B substituting 3-carbamoylphenylboronic acid for3-sulfamoylphenylboronic acid to afford 20 mg of the title compound: MS(m/z) 528.1 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.13 (s, 1H), 8.54 (s,1H), 7.94 (d, J=7.5 Hz, 1H), 7.65 (s, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.37(d, J=7.7 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.06 (s, 1H), 6.83 (s, 1H),6.65 (t, J=10.4 Hz, 2H), 6.27 (d, J=6.8 Hz, 2H), 5.45 (t, J=7.7 Hz, 1H),3.71-3.51 (m, 2H), 2.97 (d, J=7.5 Hz, 2H).

Example 328

Synthesis ofN-(1-(5-(4-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(328)

Compound 328 was prepared according to the method presented for thesynthesis of Example 301B substituting 2-(5-fluoro-1H-indol-3-yl)aceticacid for2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid toafford 4 mg of the title compound: MS (m/z) 537.1 [M+H]⁺. ¹H NMR (400MHz, cdcl₃) δ 9.77 (s, 1H), 8.33 (s, 2H), 7.30 (dt, J=9.8, 5.0 Hz, 1H),7.24-7.11 (m, 2H), 7.07-6.89 (m, 3H), 6.84 (dd, J=14.5, 8.3 Hz, 2H),6.58 (d, J=8.8 Hz, 1H), 6.82 (d, J=8.2 Hz, 2H), 5.83 (d, J=6.9 Hz, 1H),4.93-4.76 (m, 1H), 3.72-3.46 (m, 2H), 2.58 (dd, J=14.4, 4.7 Hz, 1H),1.97 (dd, J=14.4, 10.9 Hz, 1H).

Example 329

Compound 299D was purified by chiral column chromatography using aCHIRALPAK IC column eluting with heptane:ethanol (80:20). The slowesteluent (3^(rd) peak) was collected, concentrated and high vacuum driedto provide 10 mg of the title compound as a single diastereomer. MS(m/z) 576.07 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.20 (s, 1H), 8.60 (s,1H), 7.95 (d, J=2.0 Hz, 1H), 7.81 (d, J=1.9 Hz, 1H), 7.46 (d, J=3.5 Hz,1H), 6.69 (m, 1H), 6.51 (dd, J=29.0, 25.6 Hz, 2H), 6.32 (d, J=6.2 Hz,2H), 5.48 (t, J=7.4 Hz, 1H), 4.87 (s, 2H), 3.14-2.93 (m, 2H), 2.70 (dd,J=15.5, 5.5 Hz, 1H), 2.23-1.96 (m, 2H), 1.81-1.67 (m, 2H), 1.60 (m, 1H),0.90 (m, 1H), 0.65 (dd, J=10.4, 4.9 Hz, 1H).

Example 330

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-(ethoxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(330)

Compound 330 was prepared according to the method presented for thesynthesis of Example 361 substituting ethanol for methanol to afford 14mg of the title compound: MS (m/z) 606.31 [M+H]⁺. ¹H NMR (400 MHz,cd₃od) δ 8.70 (dd, J=4.9, 1.6 Hz, 1H), 7.74 (s, 1H), 7.66 (dd, J=7.8,1.6 Hz, 1H), 7.51-7.38 (m, 2H), 7.37-7.10 (m, 2H), 6.66 (dd, J=10.3, 8.1Hz, 1H), 6.31 (d, J=6.2 Hz, 2H), 5.35 (t, J=7.6 Hz, 1H), 4.92 (s, 2H),4.44 (s, 2H), 3.58-3.42 (m, 2H), 3.16-3.02 (m, 2H), 1.17 (t, J=7.0 Hz,3H).

Example 331

Synthesis of(S)—N-(1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide(331A)

Compound 331A was prepared according to the method presented for thesynthesis of Example 316 substituting2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid for2-(5-hydroxy-1H-indol-3-yl)acetic acid to afford the title compound. MS(m/z) 534.1 [M+H]⁺.

Synthesis of(S)—N-(1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide(331B)

Compound 331A (18 mg, 0.034 mmol) was dissolved in 1 mL of acetic acidand to it was added KI (22 mg, 0.14 mmol). The reaction mixture washeated up to 160° C. in a Biotage® Initiator Microwave Synthesizer for10 min. It was cooled down and the solvent was removed. The residue waspurified by reverse phase HPLC eluting with acetonitrile/water (with0.1% TFA) to afford 4.1 mg of the title compound. MS (m/z) 520.1 [M+H]⁺.¹H NMR (300 MHz, cd₃od) δ 9.09 (s, 1H), 8.44 (s, 1H), 8.01 (d, J=9.0 Hz,1H), 7.34 (d, J=8.7 Hz, 3H), 7.13 (d, J=8.5 Hz, 2H), 6.64-6.47 (m, 2H),6.32-6.15 (m, 2H), 5.36 (t, J=7.5 Hz, 1H), 3.65-3.51 (m, 2H), 2.91 (d,J=7.6 Hz, 2H).

Example 332

Synthesis of 2-(2-chloropyridin-4-yloxy)acetic acid (332A)

2-chloropyridin-4-ol (500 mg, 3.9 mmol) was dissolved in 10 mL of DMFand cooled down to 0° C. To it was added NaH (60% in oil dispersion, 187mg, 4.68 mmol) portionwise. The mixture was stirred at ambienttemperature for 20 min, a solution of tert-butyl 2-bromoacetate (683 μL,4.68 mmol) was added dropwise. It was stirred for 20 min and quenchedwith saturated aqueous NH₄Cl solution. The mixture was partitionedbetween EtOAc and water. The organic layer was separated, dried overMgSO₄, filtered and concentrated. The residue was purified by silica gelchromatography eluting with EtOAc/Hexanes to afford 742 mg of tert-butyl2-(2-chloropyridin-4-yloxy)acetate which was dissolved in 4 mL of 40% ofTFA/CH₂Cl₂ and a drop of water. The reaction mixture was stirred atambient temperature for 16 hours. The solvent was removed to provide thetitle compound. MS (m/z) 188.15 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(2-chloropyridin-4-yloxy)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(332B)

Compound 332B was prepared according to the method presented in thesynthesis of Example 54 utilizing Compound 54B and2-(2-chloropyridin-4-yloxy)acetic acid to provide 7 mg of the titlecompound. MS (m/z) 541.75 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd,J=4.9, 1.6 Hz, 1H), 8.16 (d, J=5.9 Hz, 1H), 7.69 (dd, J=7.8, 1.6 Hz,1H), 7.55-7.44 (m, 2H), 7.36 (s, 1H), 7.25 (dd, J=10.7, 8.5 Hz, 1H),7.04 (d, J=2.3 Hz, 1H), 6.95 (dd, J=5.9, 2.3 Hz, 1H), 6.74-6.60 (m, 1H),6.34 (d, J=6.2 Hz, 2H), 5.43 (t, J=7.6 Hz, 1H), 4.67 (s, 2H), 3.13-2.97(m, 2H).

Example 333

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-((methylamino)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(333)

To a mixture of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(296, 20 mg, 0.035 mmol) and methylamine hydrochloride (5 mg, 0.07 mmol)was added 1 mL of 1,2-dichloroethane followed by 10 μL of acetic acid.After the reaction mixture was stirred at ambient temperature for 10min, NaBH(OAc)₃ (9 mg, 0.042 mmol) was added, and the reaction mixturewas stirred for 16 hours. The reaction was quenched by adding NaHCO₃(saturated aqueous solution), and extracted by EtOAc. The organic layerwas separated, washed with half brine, dried over MgSO₄ and filtered.The filtrate was concentrated and purified by reverse phase HPLC elutingwith acetonitrile/water (with 0.1% TFA) to afford 9 mg of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamideas a side product and 6 mg of the title compound. MS (m/z) 591.32[M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd, J=4.7, 1.6 Hz, 1H), 7.94 (s,1H), 7.57 (dd, J=7.8, 1.7 Hz, 1H), 7.48 (d, J=7.0 Hz, 1H), 7.39 (dd,J=7.8, 4.8 Hz, 1H), 7.26 (s, 1H), 7.24-7.14 (m, 1H), 6.66 (t, J=9.2 Hz,1H), 6.32 (d, J=6.1 Hz, 2H), 5.40-5.21 (m, 1H), 4.99 (s, 2H), 4.19 (s,2H), 3.08 (qd, J=13.2, 7.7 Hz, 2H), 2.70 (s, 3H).

Example 334

Synthesis of5-(2-((1S)-1-(2-(3-(difluoromethyl)-7,7-difluoro-4-hydroxy-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(334)

Compound 334 was prepared according to the method presented for thesynthesis of Example 325 substituting Compound 285G for Compound 322 toafford 12 mg of the title compound: MS (m/z) 636.41 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.71 (d, J=4.8 Hz, 1H), 7.74-7.59 (m, 1H), 7.52-7.43 (m,1H), 7.40-7.14 (m, 3H), 7.04-6.60 (m, 2H), 6.30 (d, J=7.7 Hz, 2H), 5.35(t, J=7.5 Hz, 1H), 5.01 (s, 2H), 4.90 (s, 1H), 3.07 (m, 2H), 2.52 (m,1H), 2.18 (m, 2H), 1.95 (m, 1H).

Example 335

Synthesis of(S)-5-(2-(1-(2-(4-((cyclopropylamino)methyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(335)

Compound 335 was prepared according to the method presented for thesynthesis of Example 333 substituting cyclopropanamine for methylaminehydrochloride to afford 10 mg of the title compound: MS (m/z) 617.30[M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd, J=4.8, 1.6 Hz, 1H), 7.94 (s,1H), 7.58 (dd, J=7.8, 1.7 Hz, 1H), 7.48 (d, J=4.9 Hz, 1H), 7.40 (dd,J=7.8, 4.8 Hz, 1H), 7.33-7.10 (m, 2H), 6.72-6.55 (m, 1H), 6.33 (d, J=6.1Hz, 2H), 5.32 (dd, J=8.4, 6.6 Hz, 1H), 4.99 (s, 2H), 4.30 (s, 2H), 3.08(qd, J=13.0, 7.6 Hz, 2H), 2.85-2.68 (m, 1H), 0.99-0.73 (m, 4H).

Example 336

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-oxo-4,5-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(336)

Compound 336 was prepared according to the method presented for thesynthesis of Example 282 substituting Compound 368 for Compound 332 toafford 6 mg of the title compound: MS (m/z) 547.26 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.71 (dd, J=4.8, 1.6 Hz, 1H), 8.56 (s, 1H), 7.64-7.56 (m,1H), 7.50 (d, J=5.2 Hz, 1H), 7.45-7.38 (m, 1H), 7.36-7.12 (m, 3H),6.80-6.54 (m, 2H), 6.32 (dd, J=18.2, 6.3 Hz, 2H), 5.38-5.30 (m, 1H),5.07 (s, 2H), 3.17-2.99 (m, 2H).

Example 337

Synthesis of(S)-5-(2-(1-(2-(3-cyano-4-cyclopropyl-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(337)

Compound 337 was prepared according to the method presented for thesynthesis of Example 276 substituting Compound 359 for Compound 463 toafford 5 mg of the title compound: MS (m/z) 545.29 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.69 (dd, J=4.8, 1.6 Hz, 1H), 7.59 (dd, J=7.8, 1.7 Hz,1H), 7.47-7.37 (m, 3H), 7.35-7.10 (m, 2H), 6.65 (t, J=9.2 Hz, 1H), 6.30(d, J=6.1 Hz, 2H), 5.36-5.21 (m, 1H), 4.88-4.84 (m, 2H), 3.13-2.85 (m,2H), 1.88-1.49 (m, 1H), 1.00-0.88 (m, 2H), 0.72-0.61 (m, 2H).

Example 338

Synthesis of 2-(6-cyclopropyl-5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid (338A)

Compound 338A was prepared according to the method presented for thesynthesis of Example 360D substituting cyclopropylboronic acid formethyl boronic acid to afford the title compound MS (m/z) 245.0 [M−H]⁻.

Synthesis of(S)-3-(2-(1-(2-(6-cyclopropyl-5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(338B)

Compound 338B was prepared according to the method presented in thesynthesis of Example 50 utilizing Compound 50C and Compound 338A toprovide the title compound. MS (m/z) 582.1 [M+H]⁺.

Synthesis of(S)-3-(2-(1-(2-(6-cyclopropyl-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(338C)

Compound 338C was prepared according to the method presented for thesynthesis of Example 331 substituting Compound 338B for Compound 331A toafford 4 mg of the title compound: MS (m/z) 568.1 [M+H]⁺. 1H NMR (400MHz, cd₃od) δ 8.64 (d, J=3.7 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.70 (s,1H), 7.58 (d, J=6.7 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.42-7.17 (m, 3H),7.00 (s, 1H), 6.55 (t, J=9.1 Hz, 1H), 6.21 (d, J=6.5 Hz, 2H), 5.46 (dd,J=13.6, 6.2 Hz, 1H), 3.57 (s, 2H), 2.97 (ddd, J=19.9, 13.0, 7.5 Hz, 2H),2.20-1.96 (m, 1H), 1.05-0.81 (m, 2H), 0.59 (q, J=5.5 Hz, 2H).

Example 339

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(4-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(339A)

Compound 339A was prepared according to the method presented for thesynthesis of Example 325 substituting Compound 79 for Compound 322 toafford the title compound. MS (m/z) 618.48 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-6,7-dihydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(339B)

Compound 339A (160 mg) was dissolved in 10 mL of toluene, to it wasadded 20 mg of p-toluenesulfonic acid. The reaction mixture was stirredat ambient temperature for 16 hours then was heated up to 100° C. for 2hours. It was cooled down, and the solvent was removed. The residue waspurified by silica gel chromatography eluting with EtOAc/Hexanes toafford 108 mg of the title compound. MS (m/z) 600.46 [M+H]⁺. ¹H NMR (400MHz, cdcl₃) δ 8.50 (dd, J=4.7, 1.4 Hz, 1H), 7.57 (dd, J=7.2, 2.1 Hz,1H), 7.49-7.29 (m, 2H), 7.17 (ddd, J=32.2, 13.6, 6.6 Hz, 3H), 6.76 (d,J=9.0 Hz, 1H), 6.51-6.34 (m, 2H), 6.08 (d, J=5.8 Hz, 3H), 5.85-5.54 (m,1H), 5.37 (dd, J=14.8, 7.9 Hz, 1H), 4.67 (s, 2H), 2.94-2.73 (m, 2H),2.72-2.56 (m, 2H), 2.48-2.31 (m, 2H).

Example 340

Synthesis of ethyl2-(7,7-difluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(340A)

Compound 340A was prepared according to the method presented for thesynthesis of Example 285F substituting Compound 311A for Compound 285Eto afford the title compound. MS (m/z) 326.96 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(7,7-difluoro-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(340B)

Compound 340B was prepared according to the method presented for thesynthesis of Example 285G substituting Compound 340A for Compound 285Fto afford 9 mg of the title compound. MS (m/z) 652.32 [M+H]⁺. ¹H NMR(400 MHz, cd₃od) δ 8.74 (dd, J=4.9, 1.6 Hz, 1H), 7.70 (dd, J=7.8, 1.6Hz, 1H), 7.50 (dd, J=7.8, 5.0 Hz, 1H), 7.41 (d, J=4.9 Hz, 1H), 7.31 (s,1H), 7.21 (dd, J=10.7, 8.5 Hz, 1H), 6.67 (ddd, J=9.3, 7.0, 2.3 Hz, 1H),6.33 (d, J=6.1 Hz, 2H), 5.37 (t, J=7.6 Hz, 1H), 5.17 (s, 2H), 3.09 (d,J=7.6 Hz, 2H), 2.84-2.61 (m, 4H).

Example 341

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-ethynyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(341)

To a solution of Compound 296 (57 mg, 0.1 mmol) and dimethyl1-diazo-2-oxopropylphosphonate (31 mg, 0.16 mmol) in MeOH (0.5 mL) wasadded K₂CO₃ (34.5 mg, 0.25 mmol). The resulting solution was stirred for1 hour at ambient temperature. The reaction was then partitioned betweenEtOAc and 0.5 N HCl. The organic was dried over MgSO₄ and thenconcentrated. The crude was purified by reverse phase preparative HPLCto afford 22 mg of the product. MS (m/z) 572.29 [M+H]⁺. ¹H NMR (400 MHz,cd₃od) δ 8.70 (dd, J=4.9, 1.6 Hz, 1H), 7.94 (s, 1H), 7.64 (dd, J=7.8,1.6 Hz, 1H), 7.52-7.40 (m, 2H), 7.33 (s, 1H), 7.22 (dd, J=10.7, 8.6 Hz,1H), 6.65 (t, J=9.1 Hz, 1H), 6.30 (d, J=6.2 Hz, 2H), 5.34 (t, J=7.5 Hz,1H), 4.94 (s, 2H), 3.60 (d, J=13.7 Hz, 1H), 3.14-2.96 (m, 2H).

Example 342

Synthesis of ethyl2-(3-(trifluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetate(342A)

Compound 342 was prepared according to the method presented for thesynthesis of Example 299B substituting ethyltrifluoroacetate formethyldifluoroacetate to afford the title compound. MS (m/z) 289.26[M+H]⁺.

Synthesis of2-(3-(trifluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetic acid (342B)

Compound 342B was prepared according to the method presented in thesynthesis of Example 60G utilizing ethyl2-(3-(trifluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetateto afford the title compound. MS (m/z) 261.11 [M+H]⁺.

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(342C)

Compound 342C was prepared according to the method presented in thesynthesis of Example 54 utilizing Compound 54B and2-(3-(trifluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)aceticacid to provide 68 mg of the title compound. MS (m/z) 614.50 [M+H]⁺. ¹HNMR (400 MHz, cd₃od) δ 8.77-8.64 (m, 1H), 7.70 (t, J=6.7 Hz, 1H), 7.47(ddd, J=14.9, 7.6, 3.9 Hz, 2H), 7.35 (s, 1H), 7.23 (dd, J=10.7, 8.5 Hz,1H), 6.68 (ddd, J=7.4, 6.0, 3.4 Hz, 1H), 6.34 (dd, J=9.7, 7.4 Hz, 2H),5.38 (q, J=7.1 Hz, 1H), 4.96-4.91 (m, 2H), 3.13-2.95 (m, 2H), 2.65 (d,J=18.0 Hz, 1H), 2.25-1.98 (m, 2H), 1.94-1.52 (m, 3H), 0.96 (ddd, J=23.2,8.3, 5.2 Hz, 1H), 0.66 (td, J=10.1, 5.0 Hz, 1H).

Example 343

Synthesis of(S)-5-(2-(1-(2-(4-cyclopropyl-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(343)

Compound 343 was prepared according to the method presented for thesynthesis of Example 276 substituting(S)-5-(2-(1-(2-(4-bromo-5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(Compound 58) for(S)-5-(2-(1-(2-(4-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(Compound 463) to afford 10 mg of the title compound: MS (m/z) 616.36[M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd, J=4.9, 1.5 Hz, 1H), 7.69(dd, J=7.8, 1.6 Hz, 1H), 7.53-7.40 (m, 2H), 7.35 (s, 1H), 7.22 (dd,J=10.7, 8.5 Hz, 1H), 6.67 (t, J=9.2 Hz, 1H), 6.33 (d, J=6.2 Hz, 2H),5.35 (t, J=7.6 Hz, 1H), 4.84 (s, 2H), 3.05 (d, J=7.6 Hz, 2H), 2.76-2.46(m, 2H), 1.54 (dd, J=12.2, 6.8 Hz, 1H), 1.07 (t, J=7.6 Hz, 3H),0.92-0.80 (m, 2H), 0.53 (q, J=5.7 Hz, 2H).

Example 344

Synthesis of(S)-5-(2-(1-(2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(344)

Compound 344 was prepared according to the method presented in thesynthesis of Example 54 utilizing Compound 54B and2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid (Compound 287C) to provide 155 mg of the title compound. MS (m/z)656.52 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd, J=4.8, 1.6 Hz, 1H),7.62 (dd, J=7.8, 1.6 Hz, 1H), 7.43 (dd, J=7.8, 4.9 Hz, 1H), 7.37 (d,J=4.7 Hz, 1H), 7.30 (bs, 1H), 7.21 (dd, J=10.7, 8.5 Hz, 1H), 6.98-6.54(m, 2H), 6.31 (d, J=6.3 Hz, 2H), 5.34 (t, J=7.6 Hz, 1H), 5.06 (s, 2H),3.14-2.97 (m, 2H), 2.61-2.34 (m, 4H).

Example 345

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(3-sulfamoylphenyl)pyridin-2-yl)ethyl)-2-(4-methyl-2-oxoquinolin-1(2H)-yl)acetamide(345)

Compound 345 was prepared according to the method presented in thesynthesis of Example 55 utilizing Compound 55D and2-(4-methyl-2-oxoquinolin-1(2H)-yl)acetic acid to afford(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(4-methyl-2-oxoquinolin-1(2H)-yl)acetamide,and then Suzuki coupling with 3-sulfamoylphenylboronic acid to provide 8mg of the title compound. MS (m/z) 589.2 [M+H]⁺. ¹H NMR (400 MHz, cd₃od)δ 8.63 (d, J=4.5 Hz, 1H), 7.78 (dd, J=20.9, 7.6 Hz, 2H), 7.63 (s, 1H),7.54 (d, J=7.8 Hz, 1H), 7.44 (dd, J=14.9, 7.2 Hz, 2H), 7.34 (dd, J=7.7,4.7 Hz, 1H), 7.22 (t, J=7.6 Hz, 2H), 7.11 (d, J=8.5 Hz, 1H), 6.58 (t,J=9.2 Hz, 1H), 6.50 (s, 1H), 6.26 (d, J=6.2 Hz, 2H), 5.31 (t, J=7.5 Hz,1H), 4.96 (s, 2H), 3.06-2.92 (m, 2H), 2.43 (d, J=5.0 Hz, 3H).

Example 346

Synthesis of ethyl2-(3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-2H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-2-yl)acetate(346A)

Compound 346A was prepared according to the method presented for thesynthesis of Compound 122D substituting3-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexan-2-one for Compound 122Cafford the title compound: MS (m/z) 275.21 [M+H]⁺.

Synthesis of ethyl2-(4-oxo-3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-2H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-2-yl)acetate(346B)

Compound 346B was prepared according to the method presented in thesynthesis of Example 272A utilizing Compound 346A to provide the titlecompound. MS (m/z) 289.08 [M+H]⁺.

Synthesis of2-(4-oxo-3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-2H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-2-yl)aceticacid (346C)

Compound 346C was prepared according to the method presented for thesynthesis of Compound 60G substituting Compound 346B for Compound 60F toafford the title compound. MS (m/z) 261.08 [M+H]⁺.

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(4-oxo-3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-2H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-2-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(346D)

Compound 346D was prepared according to the method presented in thesynthesis of Example 54 utilizing Compound 54B and Compound 346C toprovide 16 mg of the title compound. MS (m/z) 614.18 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.71 (dd, J=4.9, 1.5 Hz, 1H), 7.74-7.55 (m, 1H), 7.44(ddd, J=12.7, 7.2, 4.8 Hz, 2H), 7.32 (s, 1H), 7.22 (dd, J=14.2, 5.0 Hz,1H), 6.67 (t, J=9.2 Hz, 1H), 6.33 (d, J=7.5 Hz, 2H), 5.35 (t, J=7.5 Hz,1H), 4.99 (s, 2H), 3.17-3.00 (m, 2H), 2.81 (m, 1H), 2.61 (dt, J=8.7, 4.2Hz, 1H), 1.64 (dd, J=12.7, 8.1 Hz, 1H), 1.54-1.44 (m, 1H).

Example 347

Compound 299D was purified by Chiral column chromatography usingCHIRALPAK IC column eluting with Heptane:ethanol (80:20). The fastesteluent (1st peak) was collected, concentrated and high vacuum dried toprovide 5 mg of the title compound as a mixture of diastereomers. MS(m/z) 576.07 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.20 (d, J=2.1 Hz, 1H),8.60 (s, 1H), 7.95 (s, 1H), 7.81 (d, J=1.9 Hz, 1H), 7.46 (d, J=3.5 Hz,1H), 6.69 (ddd, J=11.3, 8.5, 1.9 Hz, 1H), 6.61-6.42 (m, 2H), 6.31 (t,J=5.7 Hz, 2H), 5.48 (td, J=7.4, 3.3 Hz, 1H), 4.90 (d, J=17.7 Hz, 2H),3.13-2.87 (m, 2H), 2.70 (dd, J=15.6, 5.7 Hz, 1H), 2.26-1.98 (m, 2H),1.92-1.51 (m, 3H), 1.07-0.80 (m, 1H), 0.66 (d, J=6.6 Hz, 1H).

Example 348

Compound 299D was purified by Chiral column chromatography usingCHIRALPAK IC column eluting with Heptane:ethanol (80:20). The middle(2^(nd) peak) was collected, concentrated and high vacuum dried toprovide 10 mg of the title compound as a single diastereomer. MS (m/z)576.07 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.20 (s, 1H), 8.60 (s, 1H),7.94 (d, J=2.0 Hz, 1H), 7.81 (d, J=1.9 Hz, 1H), 7.46 (d, J=3.5 Hz, 1H),6.69 (m, 1H), 6.52 (dd, J=29.1, 25.6 Hz, 2H), 6.31 (d, J=6.2 Hz, 2H),5.47 (t, J=7.4 Hz, 1H), 4.91 (s, 2H), 3.11-2.87 (m, 2H), 2.71 (dd,J=15.7, 5.6 Hz, 1H), 2.32-1.96 (m, 2H), 1.76 (ddd, J=75.6, 39.8, 26.6Hz, 3H), 0.94 (m, 1H), 0.64 (dd, J=10.4, 4.9 Hz, 1H).

Example 349

Synthesis of ethyl2-(3-(difluoromethyl)-7-hydroxy-7-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(349A)

Ethyl2-(3-(difluoromethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetate(Compound 285C, 100 mg, 0.37 mmol) was dissolved in 5 mL of THF andcooled down to 0° C. To it was added a solution of methyllithium lithiumiodide complex (1.0 M in diethyl ether, 1.8 mL, 1.8 mmol). Afterstirring at 0° C. for 5 min, It was quenched with NH₄Cl (sat'd aqueoussolution) and extracted with EtOAc. The organic layer was separated,washed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by silica gel chromatography eluting withEtOAc/Hexanes to afford 27 mg of the title compound. MS (m/z) 288.03[M+H]⁺.

Synthesis of 5-(2-((1S)-1-(2-(3-(difluoromethyl)-7-hydroxy-7-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(349B)

Compound 349B was prepared according to the method presented in thesynthesis of Example 54 utilizing Compound 54B and2-(3-(difluoromethyl)-7-hydroxy-7-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)aceticacid to provide 31 mg of the title compound. MS (m/z) 614.02 [M+H]⁺. ¹HNMR (400 MHz, cd₃od) δ 8.74-8.64 (m, 1H), 7.78-7.59 (m, 1H), 7.53-7.41(m, 2H), 7.33 (s, 1H), 7.27-7.17 (m, 1H), 6.84-6.40 (m, 2H), 6.31 (dd,J=20.7, 6.1 Hz, 2H), 5.36 (dt, J=15.4, 7.8 Hz, 1H), 5.19 (m, 1H),5.01-4.89 (m, 1H), 3.14-2.93 (m, 2H), 2.67-2.39 (m, 2H), 2.01-1.63 (m,4H), 1.37 (d, J=5.3 Hz, 3H).

Example 350

Synthesis of(S)-5-(2-(1-(2-(4-(difluoromethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(350)

Compound 350 was prepared according to the method presented for thesynthesis of Example 150 substituting(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(Compound 296) for(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(Compound 446) to afford 26 mg of the title compound: MS (m/z) 598.10[M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.71 (dd, J=4.9, 1.6 Hz, 1H), 8.05 (s,1H), 7.66 (dd, J=7.8, 1.6 Hz, 1H), 7.55-7.38 (m, 2H), 7.34 (s, 1H), 7.22(dd, J=10.7, 8.5 Hz, 1H), 6.86 (t, J=55.2 Hz, 1H), 6.66 (dd, J=10.4, 8.1Hz, 1H), 6.31 (d, J=6.2 Hz, 2H), 5.35 (t, J=7.5 Hz, 1H), 4.99 (s, 2H),3.07 (d, J=7.6 Hz, 2H).

Example 351

Synthesis of(S)—N-(1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(351)

Compound 351 was prepared according to the method presented for thesynthesis of Example 316 substituting2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5-hydroxy-1H-indol-3-yl)acetic acid to afford 20 mg of the titlecompound: MS (m/z) 576.1 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.22 (s, 1H),8.55 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.20 (d, J=8.1 Hz, 2H), 6.74 (t,J=9.1 Hz, 1H), 6.38 (d, J=6.9 Hz, 2H), 5.45 (q, J=7.1 Hz, 1H), 4.79 (s,2H), 3.20-2.85 (m, 2H), 2.55 (t, J=5.5 Hz, 2H), 2.51-2.31 (m, 2H),1.85-1.65 (m, 4H).

Example 352

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(352)

Compound 352 was prepared according to the method presented in thesynthesis of Example 303 utilizing Compound 378 to provide 10 mg of thetitle compound. MS (m/z) 603.13 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70(dd, J=5.2, 1.5 Hz, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.61 (dd, J=7.8, 5.2Hz, 2H), 7.15 (d, J=9.2 Hz, 2H), 6.63 (t, J=9.2 Hz, 1H), 6.26 (d, J=6.1Hz, 2H), 5.29 (dd, J=9.2, 6.1 Hz, 1H), 4.94 (s, 2H), 4.33 (s, 2H), 3.39(t, J=6.3 Hz, 2H), 3.10 (dd, J=13.1, 6.3 Hz, 1H), 2.98 (dd, J=13.2, 9.3Hz, 1H), 2.86 (t, J=6.0 Hz, 2H).

Example 353

Synthesis of(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetamide(353A)

Compound 353 A was prepared according to the method presented in thesynthesis of Example 55 utilizing Compound 55D and2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid to provide thetitle compound. MS (m/z) 499.1 [M+H]⁺.

Synthesis of(S)—N-(1-(3-(3-(N-cyclopropylsulfamoyl)phenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetamide(353B)

Compound 353B was prepared according to the method presented in thesynthesis of Example 55 utilizing3-(N-cyclopropylsulfamoyl)phenylboronic acid to provide 5 mg of thetitle compound. MS (m/z) 616.2 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.00(s, 1H), 8.57 (d, J=4.7 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.47 (dd,J=17.8, 9.1 Hz, 2H), 7.39 (t, J=7.8 Hz, 2H), 7.31-7.19 (m, 2H), 7.13 (d,J=7.6 Hz, 1H), 6.48 (t, J=9.2 Hz, 1H), 6.17 (d, J=6.4 Hz, 2H), 5.15 (t,J=7.5 Hz, 1H), 5.05 (s, 2H), 3.00-2.86 (m, 2H), 2.24 (d, J=5.9 Hz, 6H),1.98-1.77 (m, 1H), 0.40-−0.11 (m, 4H).

Example 354

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(6-methyl-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(354)

Compound 354 was prepared according to the method presented for thesynthesis of Example 331B utilizing Compound 360E to afford 5 mg of thetitle compound: MS (m/z) 542.1 [M+H]⁺. ¹H NMR (400 MHz, cdcl₃) δ 8.71(m, 3H), 7.96 (d, J=7.8 Hz, 2H), 7.88 (s, 1H), 7.74 (m, 2H), 7.56-7.48(m, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.25 (s, 1H), 6.83 (d, J=7.7 Hz, 1H),6.44 (m, 2H), 6.01 (d, J=5.8 Hz, 2H), 5.66 (dd, J=16.3, 8.9 Hz, 1H),3.70 (s, 2H), 3.09-2.78 (m, 2H), 2.25 (s, 3H).

Example 355

Synthesis of(S)-5-(2-(1-(2-(4-cyclopentenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(355)

Compound 355 was prepared according to the method presented in thesynthesis of Example 276 utilizing Compound 463 and cyclopentenylboronicacid to provide 19 mg of the title compound. MS (m/z) 614.35 [M+H]⁺. ¹HNMR (400 MHz, cd₃od) δ 8.69 (dd, J=4.9, 1.6 Hz, 1H), 7.74-7.55 (m, 2H),7.52-7.39 (m, 2H), 7.34 (s, 1H), 7.21 (dd, J=10.8, 8.5 Hz, 1H), 6.65 (t,J=9.2 Hz, 1H), 6.30 (d, J=6.3 Hz, 2H), 5.96 (s, 1H), 5.35 (t, J=7.5 Hz,1H), 4.89 (s, 2H), 3.06 (d, J=7.6 Hz, 2H), 2.59 (m, 2H), 2.47 (m, 2H),2.06-1.82 (m, 2H).

Example 356

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(7-hydroxy-7-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(356)

Compound 356 was prepared according to the method presented in thesynthesis of Example 349B utilizing Compound 272B to provide 24 mg ofthe title compound. MS (m/z) 631.96 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ8.62-8.49 (m, 1H), 7.47 (ddd, J=7.7, 4.4, 1.7 Hz, 1H), 7.34-7.27 (m,2H), 7.20 (s, 1H), 7.16-7.07 (m, 1H), 6.57 (t, J=9.3 Hz, 1H), 6.21 (dd,J=24.2, 6.2 Hz, 2H), 5.37-5.22 (m, 1H), 5.16 (dd, J=16.7, 4.3 Hz, 1H),4.90 (dd, J=16.6, 2.6 Hz, 1H), 2.96 (td, J=13.0, 8.2 Hz, 2H), 2.46 (m,2H), 1.90-1.51 (m, 4H), 1.29 (d, J=2.1 Hz, 3H).

Example 357

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-(3,3-dimethylbut-1-ynyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(357)

Compound 357 was prepared according to the method presented in thesynthesis of Example 280 utilizing Compound 463 to provide 3 mg of thetitle compound. MS (m/z) 628.83 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.69(dd, J=4.8, 1.6 Hz, 1H), 7.76 (s, 1H), 7.59 (dd, J=7.8, 1.6 Hz, 1H),7.40 (dd, J=7.8, 4.8 Hz, 2H), 7.31 (s, 1H), 7.21 (dd, J=10.7, 8.6 Hz,1H), 6.65 (t, J=9.3 Hz, 1H), 6.29 (d, J=6.4 Hz, 2H), 5.40-5.28 (m, 1H),4.90 (s, 2H), 3.15-2.89 (m, 2H), 1.32-1.20 (m, 9H).

Example 358

Synthesis of(S)-3-(2-(1-(2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(358)

Compound 358 was prepared according to the method presented in thesynthesis of Example 55 utilizing Compound 55D and 22-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)acetic acid, and thenSuzuki coupling with 3-carbamoylphenylboronic acid to afford 29 mg ofthe title compound. MS (m/z) 561.8 [M+H]⁺. ¹H NMR (400 MHz, cdcl₃) δ10.08 (d, J=7.7 Hz, 1H), 8.78 (d, J=4.7 Hz, 1H), 8.12-7.96 (m, 2H),7.93-7.69 (m, 3H), 7.53 (t, J=7.7 Hz, 1H), 7.32 (m, 1H), 7.03 (m, 3H),6.63 (t, J=8.8 Hz, 1H), 6.15 (d, J=5.7 Hz, 1H), 6.05 (s, 1-), 5.65 (dd,J=16.2, 8.7 Hz, 1H), 5.15 (dd, J=39.0, 17.2 Hz, 2H), 3.17 (dd, J=13.4,6.8 Hz, 1H), 3.05 (dd, J=13.4, 9.6 Hz, 1H).

Example 359

Synthesis of(S)-5-(2-(1-(2-(4-bromo-3-cyano-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(359)

Compound 359 was prepared according to the method presented in thesynthesis of Example 56 utilizing Compound 56A and4-bromo-1H-pyrazole-3-carbonitrile to provide 6 mg of the titlecompound. MS (m/z) 585.03 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.69 (dd,J=4.8, 1.6 Hz, 1H), 7.92 (s, 1H), 7.55 (dd, J=7.8, 1.6 Hz, 1H),7.45-7.14 (m, 4H), 6.65 (t, J=9.2 Hz, 1H), 6.30 (d, J=6.3 Hz, 2H),5.40-5.28 (m, 1H), 4.97 (s, 2H), 3.15-2.95 (m, 2H).

Example 360

Synthesis of tert-butyl6-bromo-3-(2-ethoxy-2-oxoethyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-1-carboxylate(360B)

Ethyl 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetate (1.0 g, 4.26mmol) was dissolved in methylene chloride (40 mL) and cooled down to 0°C. with ice-water bath. NBS (760 mg, 4.26 mmol) was added in smallportions over 1 hour. The reaction mixture was allowed to stir at 0° C.for two more hours. Then to it were added N,N-diisopropylethylamine(1.86 mL, 8.52 mmol), di-tert-butyl carbonate (1.86 G, 8.52 mmol) and4-dimethylaminopyridine (52 mg, 0.42 mmol). The resulting mixture wasallowed to stir for overnight at ambient temperature. The reactionmixture was partitioned between methylene chloride and water. Theorganic layer was separated and dried over MgSO₄, filtered and thefiltrate was concentrated to dryness. The residue was purified by silicagel chromatography eluting with EtOAc/hexanes, and then RP-HPLC elutingwith acetonitrile/water to afford 455 mg of 360A and 131 mg of the titlecompound. MS (m/z) 414.9 [M+H]+.

Synthesis of 2-(5-methoxy-6-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)aceticacid (360D)

Compound 360B (120 mg, 0.29 mmol) and methyl boronic acid (35 mg, 0.58mmol) were dissolved in 3 mL of DMF. To it was added potassium phosphatetribasic (185 mg, 0.87 mmol) The system was degassed and purged withargon and then to it was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg,0.015 mmol). The mixture was heated up to 85° C. for 16 hours. Aftercooling down to ambient temperature the DMF solution was filtered andpurified by RP HPLC eluting with acetonitrile and water to afford 28 mgof tert-butyl3-(2-ethoxy-2-oxoethyl)-5-methoxy-6-methyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylateand 38 mg of ethyl2-(5-methoxy-6-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)acetate which wasdissolved in 1.5 mL of THF/MeOH/H₂O (3/2/1), and to it was addedLiOH.H₂O (30 mg). The reaction mixture was allowed to stir at ambienttemperature for 20 min and purified by RP-HPLC eluting with acetonitrileand water to afford 15 mg of the title compound. MS (m/z) 221.2 [M+H]⁺.

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(5-methoxy-6-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(360E)

Compound 360E was prepared according to the method presented in thesynthesis of Example 50 utilizing Compound 50C and2-(5-methoxy-6-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid toprovide 4 mg of the title compound. MS (m/z) 556.1 [M+H]⁺. ¹H NMR (400MHz, cdcl₃) δ 9.77 (s, 1H), 8.81 (s, 1H), 8.62 (s, 1H), 7.93 (d, J=7.6Hz, 2H), 7.76 (s, 3H), 7.53 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.23 (s,1H), 6.96 (d, J=7.7 Hz, 1H), 6.41 (d, J=9.5 Hz, 2H), 6.02 (d, J=6.3 Hz,2H), 5.61 (d, J=8.1 Hz, 1H), 4.08 (s, 3H), 3.76 (s, 2H), 2.94 (s, 2H),2.23 (s, 3H).

Example 361

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-(methoxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(361)

Compound 296 (20 mg, 0.03 mmol) was dissolved in 1 mL of methanol and toit was added decaborane (8.5 mg, 0.06 mmol). The reaction mixture wasstirred at ambient temperature for 3 days. It was quenched with NaHCO₃(sat'd aqueous solution) and extracted with EtOAc. The organic layer wasseparated, washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by reverse phase HPLC elutingwith acetonitrile/water (with 0.1% TFA) to afford 9.1 mg of the titlecompound. MS (m/z) 592.23 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.69 (dd,J=4.8, 1.6 Hz, 1H), 7.74 (s, 1H), 7.64 (dd, J=7.8, 1.6 Hz, 1H),7.49-7.36 (m, 2H), 7.30 (bs, 1H), 7.21 (dd, J=10.7, 8.5 Hz, 1H), 6.65(dd, J=10.4, 8.1 Hz, 1H), 6.30 (d, J=6.2 Hz, 2H), 5.34 (t, J=7.5 Hz,1H), 4.92 (s, 2H), 4.39 (s, 2H), 3.33 (s, 2H), 3.12-3.00 (m, 2H).

Example 362

Synthesis of(S)-2-(2-(3,5-difluorophenyl)-1-(2-(4-methyl-2-oxoquinolin-1(2H)-yl)acetamido)ethyl)-3,4′-bipyridine-2′-carboxamide(362)

Compound 362 was prepared according to the method presented in thesynthesis of Example 310 utilizing 2-(4-methyl-2-oxoquinolin-1(2H)-yl)acetic acid to provide 9 mg of the title compound. MS (m/z)554.5 [M+H]⁺. ¹H NMR (400 MHz, cd3od) δ 8.79 (d, J=4.7 Hz, 1H), 8.59 (d,J=5.0 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.73-7.61 (m, 2H), 7.51 (ddd,J=12.7, 10.7, 5.1 Hz, 3H), 7.31 (t, J=7.5 Hz, 1H), 7.21 (d, J=8.5 Hz,1H), 6.66 (t, J=9.3 Hz, 1H), 6.59 (s, 1H), 6.32 (d, J=6.4 Hz, 2H), 5.35(t, J=7.6 Hz, 1H), 5.07 (q, J=16.7 Hz, 2H), 3.19-3.04 (m, 2H), 2.52 (s,3H).

Example 363

Synthesis of(S)-5-(2-(1-(2-(4-cyano-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(363)

(S)-5-(2-(1-(2-(4-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(Compound 463, 20 mg, 0.03 mmol) was dissolved in 0.5 mL of DMF. To itwas added CuCN (5.7 mg, 0.06 mmol) and the reaction mixture was heatedup to 200° C. for 16 hours. It was cooled down and partitioned betweenEtOAc and 5% LiCl aqueous solution. The organic layer was separated,washed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified by reverse phase HPLC eluting withacetonitrile/water (with 0.1% TFA) to afford 6.5 mg of the titlecompound. MS (m/z) 573.22 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70 (dd,J=4.8, 1.6 Hz, 1H), 8.43 (s, 1H), 7.61 (dd, J=7.8, 1.7 Hz, 1H), 7.42(dd, J=7.8, 4.9 Hz, 2H), 7.31 (s, 1H), 7.21 (dd, J=10.7, 8.5 Hz, 1H),6.65 (t, J=9.2 Hz, 1H), 6.31 (d, J=6.2 Hz, 2H), 5.41-5.23 (m, 1H), 5.04(s, 2H), 3.09 (dd, J=16.5, 9.7 Hz, 2H).

Example 364

Synthesis of 5-(2-((1S)-1-(2-(4,4-difluoro-3-(trifluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(364)

Compound 364 was prepared according to the method presented in thesynthesis of Example 304 utilizing Compound 342A to provide 2 mg of thetitle compound. MS (m/z) 650.00 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ8.78-8.62 (m, 1H), 7.58 (dd, J=7.8, 1.7 Hz, 1H), 7.49-7.13 (m, 4H), 6.66(d, J=6.8 Hz, 1H), 6.34 (dd, J=12.9, 6.6 Hz, 2H), 5.37 (t, J=7.4 Hz,1H), 5.11-4.92 (m, 2H), 3.07 (m, 2H), 2.63 (t, J=16.6 Hz, 1H), 2.28 (m,1H), 1.94-1.77 (m, 2H), 1.16 (m, 1H), 0.46 (m, 1H).

Example 365

Synthesis of(S)—N-(1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(365)

Compound 365 was prepared according to the method presented for thesynthesis of Example 279G substituting Compound 279D and2-(5-fluoro-1H-indol-3-yl)acetic acid for Compound 279E and2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid to afford 22 mg ofthe title compound: MS (m/z) 521.1 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ9.13 (s, 1H), 8.48 (s, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.28 (dd, J=8.8, 4.3Hz, 1H), 7.19-7.10 (m, 4H), 6.84 (t, J=8.9 Hz, 1H), 6.68 (t, J=9.2 Hz,1H), 6.33 (d, J=6.6 Hz, 2H), 5.42 (q, J=7.1 Hz, 1H), 3.69-3.44 (m, 2H),2.99 (d, J=7.5 Hz, 2H).

Example 366

Synthesis of(S)-5-(2-(1-(2-(3-bromo-5-cyclopropyl-1H-1,2,4-triazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(366)

Compound 366 was prepared according to the method presented in thesynthesis of Example 56 utilizing Compound 56A and3-bromo-5-cyclopropyl-1H-1,2,4-triazole to provide 6 mg of the titlecompound. MS (m/z) 599.90 [M+H]⁺. H NMR (400 MHz, cd₃od) δ 8.71 (dd,J=4.9, 1.6 Hz, 1H), 7.66 (dd, J=7.8, 1.6 Hz, 1H), 7.46 (dd, J=7.8, 4.9Hz, 2H), 7.33 (s, 1H), 7.23 (dd, J=10.7, 8.5 Hz, 1H), 6.67 (dd, J=10.4,8.0 Hz, 1H), 6.34 (d, J=6.1 Hz, 2H), 5.36 (t, J=7.6 Hz, 1H), 4.97 (s,2H), 3.08 (d, J=7.6 Hz, 2H), 1.88 (m, 1H), 1.12-0.74 (m, 4H).

Example 367

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(2-methyl-1H-indol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(367)

Compound 367 was prepared according to the method presented in thesynthesis of Example 54 utilizing Compound 54B and 32-(2-methyl-1H-indol-1-yl)acetic acid to provide 20 mg of the titlecompound. MS (m/z) 525.2 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.60 (d,J=4.8 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.65-7.55 (m, 2H), 7.53-7.33 (m,3H), 7.28 (d, J=7.8 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 7.06-6.94 (m, 2H),6.66 (t, J=9.2 Hz, 1H), 6.25 (s, 3H), 5.46 (t, J=7.4 Hz, 1H), 4.80 (s,2H), 2.93 (qd, J=13.0, 7.3 Hz, 2H), 2.30 (s, 3H).

Example 368

Synthesis of(S)-5-(2-(1-(2-(4-chloro-1H-imidazo[4,5-c]pyridin-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(368)

Compound 368 was prepared according to the method presented for thesynthesis of Example 332 substituting 4-chloro-1H-imidazo[4,5-c]pyridinefor 2-chloropyridin-4-ol to afford 6 mg of the title compound: MS (m/z)565.60 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.65 (dd, J=4.8, 1.6 Hz, 1H),8.31 (s, 1H), 8.07 (t, J=6.2 Hz, 1H), 7.65-7.49 (m, 1H), 7.50-7.35 (m,3H), 7.22 (s, 1H), 7.12 (dd, J=10.8, 8.5 Hz, 1H), 6.59 (dd, J=10.4, 8.0Hz, 1H), 6.28 (t, J=9.0 Hz, 2H), 5.33-5.16 (m, 1H), 5.05 (s, 2H), 3.03(m, 2H).

Example 369

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(6,6-dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(369)

Compound 369 was prepared according to the method presented in thesynthesis of Example 56 utilizing Compound 56A and6,6-dimethyl-3-(trifluoromethyl)-6,7-dihydro-1H-indazol-4(5H)-one toprovide 4 mg of the title compound. MS (m/z) 644.36 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.70 (d, J=3.2 Hz, 1H), 7.56 (d, J=6.1 Hz, 1H), 7.46-7.30(m, 3H), 7.21 (d, J=10.7 Hz, 1H), 6.66 (m, 1H), 6.35 (d, J=6.0 Hz, 2H),5.34 (m, 1H), 4.93 (s, 2H), 3.18-2.93 (m, 2H), 2.65 (s, 2H), 2.37 (s,2H), 1.06 (d, J=2.9 Hz, 6H).

Example 370

Synthesis of(S)-5-(2-(1-(2-(3-(difluoromethyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(370)

Compound 370 was prepared according to the method presented in thesynthesis of Example 54 utilizing Compound 54B and Compound 285C toprovide 11 mg of the title compound. MS (m/z) 598.36 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.74 (dd, J=5.0, 1.6 Hz, 1H), 7.72 (dd, J=7.8, 1.6 Hz,1H), 7.51 (dd, J=7.8, 5.0 Hz, 1H), 7.45-7.26 (m, 2H), 7.20 (dd, J=10.7,8.6 Hz, 1H), 6.98-6.51 (m, 2H), 6.31 (d, J=6.1 Hz, 2H), 5.35 (t, J=7.6Hz, 1H), 5.25-5.09 (m, 2H), 3.06 (dd, J=11.7, 10.1 Hz, 2H), 2.87 (t,J=6.0 Hz, 2H), 2.61-2.38 (m, 2H), 2.23-2.03 (m, 2H).

Example 371

Synthesis of(S)—N-(1-(6′-amino-5′-(trifluoromethyl)-3,3′-bipyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(371)

Compound 371 was prepared according to the method presented in thesynthesis of Example 287E utilizing Compound 287D and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amineto provide 15 mg of the title compound. MS (m/z) 679.35 [M+H]⁺. ¹H NMR(400 MHz, cd₃od) δ 8.74 (dd, J=4.8, 1.6 Hz, 1H), 7.99 (s, 1H), 7.63-7.50(m, 2H), 7.42 (dd, J=7.8, 4.8 Hz, 1H), 7.03-6.56 (m, 2H), 6.37 (d, J=6.2Hz, 2H), 5.25 (t, J=7.6 Hz, 1H), 5.16-4.94 (m, 2H), 3.12 (d, J=7.7 Hz,2H), 2.75-2.30 (m, 4H).

Example 372

Synthesis of(S)-5-(2-(1-(2-(4-cyano-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-(dimethylamino)benzamide(372)

Compound 372 was prepared according to the method presented in thesynthesis of Example 363 utilizing Compound 275 to provide Compound 376and 12 mg of the title compound as a side product. MS (m/z) 612.31[M+H]⁺. ¹H NMR (400 MHz, cd3cn) δ 8.76 (dd, J=4.8, 1.5 Hz, 1H), 7.92 (s,1H), 7.73 (d, J=8.4 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.46 (dd, J=7.8,4.8 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 6.79-6.60 (m, 1H), 6.28 (d, J=6.5Hz, 2H), 5.53 (m, 1H), 5.07-4.83 (m, 2H), 3.18 (s, 6H), 3.02 (ddd,J=22.0, 13.0, 7.7 Hz, 2H), 2.38 (s, 3H).

Example 373

Synthesis of(S)—N-(1-(3-(3-cyano-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(7-methoxynaphthalen-1-yl)acetamide(373)

Compound 373 was prepared according to the method presented in thesynthesis of Example 55 utilizing Compound 55D and2-(7-methoxynaphthalen-1-yl)acetic acid to afford(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(7-methoxynaphthalen-1-yl)acetamide,and then Suzuki coupling with 3-cyano-4-fluorophenylboronic acid toprovide 6 mg of the title compound. MS (m/z) 552.2 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.64 (d, J=4.9 Hz, 1H), 7.74 (dd, J=17.6, 8.5 Hz, 2H),7.58 (d, J=7.8 Hz, 1H), 7.42 (dd, J=7.8, 4.9 Hz, 2H), 7.34 (s, 1H),7.32-7.24 (m, 3H), 7.21 (d, J=2.1 Hz, 1H), 7.11 (dd, J=9.0, 2.4 Hz, 1H),6.70 (t, J=9.1 Hz, 1H), 6.25 (d, J=6.3 Hz, 2H), 5.35-5.16 (m, 1H), 3.98(q, J=15.5 Hz, 2H), 3.79 (s, 3H), 3.09-2.87 (m, 2H).

Example 374

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(374)

Compound 374 was prepared according to the method presented in thesynthesis of Example 56 utilizing Compound 56A and5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazole to provide 40 mg of thetitle compound. MS (m/z) 563.32 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.72(dd, J=4.9, 1.5 Hz, 1H), 7.67 (dd, J=7.8, 1.6 Hz, 1H), 7.47 (dd, J=7.8,4.9 Hz, 2H), 7.32 (s, 1H), 7.22 (dd, J=10.7, 8.6 Hz, 1H), 6.78-6.49 (m,1H), 6.34 (d, J=6.2 Hz, 2H), 5.36 (t, J=7.6 Hz, 1H), 5.02 (d, J=17.1 Hz,2H), 3.09 (d, J=7.6 Hz, 2H), 2.39 (s, 3H).

Example 375

Synthesis of(S)—N-(1-(6′-amino-3,3′-bipyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(375)

Compound 375 was prepared according to the method presented in thesynthesis of Example 287E utilizing 287D and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine toprovide 11 mg of the title compound. MS (m/z) 611.34 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.74 (dd, J=4.7, 1.6 Hz, 1H), 7.64-7.50 (m, 3H), 7.39 (dd,J=7.8, 4.8 Hz, 1H), 7.03-6.88 (m, 1H), 6.81-6.61 (m, 2H), 6.42 (d, J=6.3Hz, 2H), 5.27 (t, J=7.6 Hz, 1H), 5.14-4.99 (m, 2H), 3.12 (d, J=7.7 Hz,2H), 2.70-2.34 (m, 4H).

Example 376

Synthesis of(S)-5-(2-(1-(2-(4-cyano-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(376)

Compound 376 was prepared according to the method presented in thesynthesis of Example 363 utilizing Compound 275 to provide 7 mg of thetitle compound. MS (m/z) 587.28 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.71(dd, J=4.9, 1.6 Hz, 1H), 7.65 (dd, J=7.8, 1.6 Hz, 1H), 7.45 (dd, J=7.8,4.9 Hz, 2H), 7.32 (s, 1H), 7.22 (dd, J=10.7, 8.6 Hz, 1H), 6.67 (t, J=9.2Hz, 1H), 6.33 (d, J=6.2 Hz, 2H), 5.35 (t, J=7.6 Hz, 1H), 4.99 (s, 2H),3.08 (d, J=7.7 Hz, 2H), 2.36 (s, 3H).

Example 377

Synthesisof(S)—N-(1-(2′-cyano-3,4′-bipyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(377)

Compound 377 was prepared according to the method presented in thesynthesis of Example 55 utilizing Compound 55E and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile toprovide 5 mg of the title compound. MS (m/z) 512.1 [M+H]⁺. ¹H NMR (400MHz, cdcl₃) δ 8.83 (d, J=5.0 Hz, 1H), 8.62 (d, J=4.2 Hz, 1H), 8.24 (s,1H), 8.09 (d, J=7.1 Hz, 1H), 7.91-7.79 (m, 1H), 7.69 (m, 2H), 7.30 (m,1H), 7.22 (d, J=2.2 Hz, 1H), 6.94 (m, 1H), 6.84 (dd, J=9.4, 2.3 Hz, 1H),6.69 (t, J=8.7 Hz, 1H), 6.11 (m, 2H), 5.36-5.12 (m, 1H), 3.70 (q, J=16.3Hz, 2H), 3.06 (dd, J=13.5, 6.3 Hz, 1H), 2.94 (dd, J=13.4, 9.9 Hz, 1H).

Example 378

Synthesis of (S)-tert-butyl1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate(378)

Compound 378 was prepared according to the method presented in thesynthesis of Example 56 utilizing 56A and tert-butyl3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylateto provide 6 mg of the title compound. MS (m/z) 703.14 [M+H]⁺. ¹H NMR(400 MHz, cd₃od) δ 8.69 (d, J=4.8 Hz, 1H), 7.64-7.50 (m, 1H), 7.37 (m,3H), 7.25-7.15 (m, 1H), 6.64 (m, 1H), 6.30 (d, J=6.3 Hz, 2H), 5.33 (m,1H), 4.85 (s, 2H), 4.46 (s, 2H), 3.18-2.93 (m, 4H), 2.63 (m, 2H), 1.45(s, 9H).

Example 379

Synthesis ofN—((S)-1-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetamide(379)

Compound 379 was prepared according to the method presented in thesynthesis of Example 61F utilizing Compound 342B and Compound 61E toprovide 19 mg of the title compound. MS (m/z) 593.42 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.86-8.64 (m, 1H), 8.09 (s, 1H), 7.96 (m, 1H), 7.70 (m,1H), 7.63 (d, J=3.5 Hz, 1H), 7.54-7.38 (m, 1H), 6.81-6.58 (m, 2H), 6.30(m, 2H), 5.33 (m, 1H), 4.93 (m, 2H), 3.23-2.96 (m, 2H), 2.65 (m, 1H),2.15 (m, 2H), 1.88-1.47 (m, 3H), 1.09-0.76 (m, 1H), 0.66 (m, 1H).

Example 380

Synthesis of(S)-5-(2-(1-(2-(3-(difluoromethyl)-7,7-difluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(380)

Compound 380 was prepared according to the method presented in thesynthesis of Example 54 utilizing Compound 54B and Compound 285E toprovide 40 mg of the title compound. MS (m/z) 620.40 [M+H]⁺. ¹H NMR (400MHz, cd₃od) δ 8.71 (dd, J=5.0, 1.6 Hz, 1H), 7.71 (dd, J=7.8, 1.6 Hz,1H), 7.50 (dd, J=7.8, 5.0 Hz, 1H), 7.44-7.28 (m, 2H), 7.22 (dd, J=10.7,8.5 Hz, 1H), 6.94-6.53 (m, 2H), 6.32 (m, 2H), 5.35 (t, J=7.6 Hz, 1H),5.01 (m, 2H), 3.05 (d, J=7.6 Hz, 2H), 2.67 (m, 2H), 2.35-2.04 (m, 2H),2.05-1.80 (m, 2H).

Example 381

Synthesis of 5-(2-((1S)-1-(2-(4,4-difluoro-3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-2H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-2-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(381)

Compound 381 was prepared according to the method presented in thesynthesis of Example 304 utilizing Compound 346B to provide 41 mg of thetitle compound. MS (m/z) 636.38 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.71(dd, J=4.9, 1.6 Hz, 1H), 7.74-7.60 (m, 1H), 7.49-7.29 (m, 3H), 7.27-7.15(m, 1H), 6.67 (t, J=9.2 Hz, 1H), 6.32 (d, J=8.1 Hz, 2H), 5.35 (t, J=7.5Hz, 1H), 4.94 (s, 2H), 3.05 (d, J=7.6 Hz, 2H), 2.72-2.41 (m, 2H), 1.41(dd, J=14.1, 7.6 Hz, 1H), 1.06 (m, 1H).

Example 382

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(382)

Compound 382 was prepared according to the method presented in thesynthesis of Example 56 utilizing Compound 286 and3-carbamoylphenylboronic acid to provide 8 mg of the title compound. MS(m/z) 516.2 [M+H]⁺. ¹H NMR (400 MHz, cdcl₃) δ 9.97 (d, J=8.3 Hz, 1H),8.67 (m, 2H), 7.98-7.71 (m, 3H), 7.61 (m, 1H), 7.46-7.21 (m, 2H), 6.92(m, 1H), 6.51 (t, J=8.8 Hz, 2H), 6.13 (d, J=6.0 Hz, 2H), 5.53 (d, J=8.2Hz, 1H), 4.78 (m, 2H), 3.15-2.86 (m, 2H), 2.51 (m, 2H), 2.30 (m, 2H),1.73 (m, 4H).

Example 383

Synthesis(R)—N-(1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(383)

Compound 383 was prepared according to the method presented for thesynthesis of Example 279G substituting2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acidfor 2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid to afford 20 mgof the title compound: MS (m/z) 576.1 [M+H]⁺. ¹H NMR (400 MHz, cdcl₃) δ9.17 (s, 1H), 8.57 (s, 1H), 7.48 (m, 3H), 7.09 (d, J=8.2 Hz, 2H), 6.60(t, J=8.8 Hz, 1H), 6.17 (d, J=6.1 Hz, 2H), 5.53 (dd, J=15.1, 7.5 Hz,1H), 4.72 (s, 2H), 2.83 (d, J=7.2 Hz, 2H), 2.68-2.42 (m, 4H), 1.80 (dd,J=26.2, 5.4 Hz, 4H).

Example 384

Synthesis of 5-(2-((1S)-1-(2-(3-(difluoromethyl)-7-hydroxy-4,5,6,7-tetrahydro-H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(384)

Compound 384 was prepared according to the method presented for thesynthesis of Example 325 utilizing Compound 370 to afford 15 mg of thetitle compound. MS (m/z) 600.20 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70(d, J=5.0 Hz, 1H), 7.71 (td, J=8.5, 1.6 Hz, 1H), 7.49 (m, 2H), 7.34 (s,1H), 7.22 (m, 1H), 6.81-6.47 (m, 2H), 6.31 (dd, J=9.5, 7.3 Hz, 2H),5.47-5.20 (m, 1H), 5.07-4.86 (m, 2H), 4.70 (m, 1H), 3.12-2.95 (m, 2H),2.82-2.26 (m, 2H), 1.99-1.55 (m, 4H).

Example 385

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(385)

Compound 385 was prepared according to the method presented in thesynthesis of Example 56 utilizing Compound 56A and5-methyl-3-(trifluoromethyl)-1H-pyrazole to provide 33 mg of the titlecompound. MS (m/z) 599.90 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.71 (dd,J=4.9, 1.6 Hz, 1H), 7.68 (dd, J=7.8, 1.6 Hz, 1H), 7.54-7.43 (m, 2H),7.34 (s, 1H), 7.22 (dd, J=10.7, 8.5 Hz, 1H), 6.67 (tt, J=9.2, 2.3 Hz,1H), 6.43-6.18 (m, 3H), 5.37 (t, J=7.5 Hz, 1H), 4.88 (s, 2H), 3.07 (d,J=7.6 Hz, 2H), 2.20 (s, 3H).

Example 386

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(3-sulfamoylphenyl)pyridin-2-yl)ethyl)-2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetamide(386)

Compound 386 was prepared according to the method presented in thesynthesis of Example 353 substituting 3-sulfamoylphenylboronic acid for3-(N-cyclopropylsulfamoyl)phenylboronic acid to provide 10 mg of thetitle compound. MS (m/z) 616.2 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 9.23(s, 1H), 8.77 (d, J=4.8 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.76-7.51 (m,4H), 7.49-7.38 (m, 2H), 7.29 (d, J=7.8 Hz, 1H), 6.66 (t, J=9.2 Hz, 1H),6.36 (d, J=6.5 Hz, 2H), 5.37 (t, J=7.6 Hz, 1H), 5.27 (s, 2H), 3.15 (m,2H), 2.45 (d, J=3.0 Hz, 6H).

Example 387

Synthesis of(S)-5-(2-(1-(2-(6,6-difluoro-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(387)

Compound 387 was prepared according to the method presented in thesynthesis of Example 150 utilizing Compound 322 to provide 2 mg of thetitle compound. MS (m/z) 638.06 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.70(dd, J=4.9, 1.6 Hz, 1H), 7.74-7.61 (m, 1H), 7.46 (m, 2H), 7.35 (s, 1H),7.22 (m, 1H), 6.72-6.56 (m, 1H), 6.34 (d, J=6.2 Hz, 2H), 5.36 (t, J=7.6Hz, 1H), 4.84 (s, 2H), 3.15-2.96 (m, 4H), 2.75 (t, J=6.5 Hz, 2H), 2.20(tt, J=13.4, 6.5 Hz, 2H).

Example 388

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(388)

Compound 388 was prepared according to the method presented in thesynthesis of Example 324 utilizing Compound 352 to provide 22 mg of thetitle compound. MS (m/z) 617.37 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.71(dd, J=4.8, 1.3 Hz, 1H), 7.61 (m, 2H), 7.49-7.33 (m, 1H), 7.30-6.98 (m,2H), 6.77-6.52 (m, 1H), 6.31 (d, J=6.2 Hz, 2H), 5.31 (m, 1H), 5.00-4.89(m, 2H), 4.48 (bs, 2H), 3.58 (bs, 2H), 3.23-2.93 (m, 7H).

Example 389

Synthesis of(S)-1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-N-methoxy-N-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide(389A)

To a mixture of Compound 323 (222 mg, 0.38 mmol) andN,O-dimethylhydroxylamine hydrochloride (73 mg, 0.75 mmol) were addedtriethylamine (159 μL, 1.1 mmol) and HATU (217 mg, 0.57 mmol). Thereaction was allowed to stir at ambient temperature for 1 hour, and thenpartitioned between CH₂Cl₂ and 5% LiCl aqueous solution. The organiclayer was separated, washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was dissolved in CH₂Cl₂ and to it was addedhexanes. The resulting precipitate was collected by vacuum filtrationand then high vacuum dried to afford 220 mg of the title compound. MS(m/z) 635.36 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(4-acetyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(389B)

Compound 389 A (120 mg, 0.19 mmol) was dissolved in 5 mL of THF and toit was added MeMgBr (3.0 M in diethyl ether, 0.67 mL, 2 mmol) and thereaction mixture was stirred at ambient temperature for 20 min. It wasquenched with ice and 1 N HCl and extracted with EtOAc. The organiclayer was separated, washed with brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by reverse phase HPLC elutingwith acetonitrile/water (with 0.1% TFA) to afford 25 mg of the titlecompound. MS (m/z) 590.09 [M+H]⁺. ¹H NMR (400 MHz, cdcl₃) δ 10.00 (d,J=7.3 Hz, 1H), 8.91-8.67 (m, 1H), 8.10-7.96 (m, 2H), 7.80 (m, 2H), 7.61(d, J=6.1 Hz, 1H), 7.31 (dd, J=11.2, 8.6 Hz, 1H), 6.90 (m, 1H), 6.61 (m,2H), 6.21 (d, J=5.7 Hz, 2H), 5.47 (dd, J=16.0, 7.4 Hz, 1H), 4.91 (q,J=16.2 Hz, 2H), 3.20 (dd, J=13.6, 7.1 Hz, 1H), 3.03 (dd, J=13.5, 9.0 Hz,1H), 2.45 (s, 3H).

Example 390

Synthesis of5-(2-(1-(2-(3-(difluoromethyl)-4,7,7-trifluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(390)

Compound 390 was prepared according to the method presented in thesynthesis of Example 150 utilizing Compound 334 to provide 17 mg of thetitle compound. MS (m/z) 638.19 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.71(d, J=4.9 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.51-7.41 (m, 1H), 7.39-7.26(m, 2H), 7.21 (dd, J=10.7, 8.6 Hz, 1H), 6.98-6.55 (m, 2H), 6.31 (d,J=6.7 Hz, 2H), 5.72 (d, 1H), 5.35 (t, J=6.7 Hz, 1H), 5.13-4.97 (m, 2H),3.07 (m, 2H), 2.68-2.05 (m, 4H).

Example 391

Synthesis of5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(6-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(391)

Compound 391 was prepared according to the method presented for thesynthesis of Example 325 utilizing Compound 281C to afford 15 mg of thetitle compound: MS (m/z) 604.36 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.71(dt, J=4.9, 1.6 Hz, 1H), 7.70 (td, J=8.5, 1.6 Hz, 1H), 7.48 (m, 2H),7.33 (bs, 1H), 7.22 (m, 1H), 6.66 (td, J=9.3, 7.0 Hz, 1H), 6.30 (dd,J=8.3, 6.3 Hz, 2H), 5.36 (dd, J=15.6, 8.1 Hz, 1H), 5.07 (dt, J=7.2, 3.5Hz, 1H), 4.95-4.76 (m, 2H), 3.15-2.98 (m, 2H), 2.97-2.70 (m, 2H),2.68-2.46 (m, 1H), 2.36 (m, 1H).

Example 392

Synthesis of5-(2-(1-(2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(392)

Compound 392 was prepared according to the method presented in thesynthesis of Example 54 utilizing Compound 54B and2-(3-(difluoromethyl)-5,5a,6,6a-tetrahydrocyclopropa[g]indazol-1(4H)-yl)aceticacid (Compound 299C) to provide 22 mg of the title compound. MS (m/z)596.43 [M+H]⁺. ¹H NMR (400 MHz, cd₃od) δ 8.82-8.57 (m, 1H), 7.68 (dd,J=8.9, 3.8 Hz, 1H), 7.54-7.41 (m, 2H), 7.34 (bs, 1H), 7.30-7.13 (m, 1H),6.83-6.42 (m, 2H), 6.33 (m, 2H), 5.37 (dd, J=13.4, 7.6 Hz, 1H),4.97-4.73 (m, 2H), 3.14-2.98 (m, 2H), 2.70 (d, J=14.7 Hz, 1H), 2.24-1.93(m, 2H), 1.94-1.48 (m, 3H), 0.93 (m, 1H), 0.64 (m, 1H).

Example 393

Synthesis of(S)—N-(1-(3-(4-(N-butylsulfamoyl)phenyl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(393)

Prepared 2.5 mg of the title compound by a method analogous to 68B using68A and 4-(N-butylsulfamoyl)phenylboronic acid. MS (m/z) 692 [M+H]⁺.

Example 394

Synthesis of((S)—N-(1-(3-(4-acetamidophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(394)

Prepared 37.1 mg of the title compound by a method analogous to 55Fusing 4-(acetamidophenyl)boronic acid and 55E. MS (m/z) 543 [M+H]⁺.

Example 395

Synthesis of(S)—N-(1-(3-(2-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(395)

Prepared 37.1 mg of the title compound by a method analogous to 55Fusing 2-chlorophenylboronic acid and 55E. MS (m/z) 520 [M+H]⁺.

Example 396

Synthesis of(S)—N-(1-(3-(3,4-dichlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(396)

Prepared 15.4 mg of the title compound by a method analogous to 55Fusing 3,4-dichloro-phenylboronic acid and 55E. MS (m/z) 554 [M+H]⁺.

Example 397

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4,5,6,7-tetrahydro-3-difluoromethyl-4-oxo-5,7-(methano)indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(397)

To a solution of Compound 87 (20.7 mg, 0.029 mmol) in acetic acid (1 ml)was added CrO₃ (8.7 mg, 0.087 mmol). The reaction mixture was stirred atroom temperature for 7 days and then filtered. The filtrate was purifiedby RP HPLC using a C18 column with a gradient of 0.1%TFA-acetonitrile/0.1%/H₂O to give 10.3 mg of the title compound. MS(m/z) 610 [M+H]⁺.

Example 398

Synthesis of(S)—N-(1-(3-(biphenyl-2-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(398)

Prepared 36.3 mg of the title compound by a method analogous to 55Fusing 2-phenyl-phenylboronic acid and 55E. MS (m/z) 562 [M+H]⁺.

Example 399

Synthesis of((S)—N-(2-(3,5-difluorophenyl)-1-(6′-fluoro-5′-methyl-3,3′-bipyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(399)

Prepared 31.9 mg of the title compound by analogous method to 55F using3-acetylphenylboronic acid and 55E. MS (m/z) 519 [M+H]⁺.

Example 400

Synthesis of(S)—N-(1-(3-(oxindole-5-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[e]pyrazol-1(4H)-yl)acetamide(400)

Prepared 4.8 mg of the title compound by a method analogous to 68B using68A and oxindole-5-boronic acid, pinacol ester. MS (m/z) 612 [M+H]⁺.

Example 401

Synthesis of (S)-methyl3-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzoate(401A)

Prepared 480 mg of the title compound by a method analogous to 57B using3-carbomethoxy-phenylboronic acid and 57A. MS (m/z) 599 [M+H]⁺.

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzoicacid (401B)

Dissolved 410A (480 mg, 0.803 mmol) in THF (4 ml) and MeOH (2 ml). Added2.5N aq LiOH and stirred for 45 min. at room temperature. The reactionwas acidified to pH=6 with 20 mM KH₂PO₄. The mixture was extracted 3×EtOAc. The combined organics were washed with brine, dried over MgSO₄,filtered and concentrated. The residue was dried under reduced pressureto give 348 mg of the title compound. MS (m/z) 585 [M+H]⁺.

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-N-(2-(dimethylamino)ethyl)benzamide(401C)

Dissolved 401B (30 mg, 0.051 mmol) in 1 ml of DMF. AddedN,N-dimethylaminoethylamine (16.8 uL, 0.153 mmol) followed by HATU (21mg, 0.056 mmol). Stirred the reaction for 1 hr at room temperature.Filtered reaction and purified filtrate by RP HPLC using a C18 columnwith a gradient of 0.1%/H₂O, 0.1% TFA-acetonitrile to give 24.1 mg ofthe title compound. ¹H NMR (400 MHz, CD₃OD) δ 8.71 (d, 1H), 7.89 (d,1H), 7.72 (s, 1H), 7.62 (d, 1H), 7.52 (t, 1H), 7.40 (dd, 1H), 7.23 (d,1H), 6.68 (t, 1H), 6.26 (d, 2H), 5.52 (t, 1H), 3.66 (d, 2H), 3.01 (dd,2H), 2.89 (d, 5H), 2.55 (s, 2H), 2.42 (d, 2H), 1.76 (s, 4H). MS (m/z)655 [M+H]⁺.

Example 402

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-phenylpyridin-2-yl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(402)

Prepared 44 mg of the title compound by a method analogous to 113 usingphenylboronic acid ¹H NMR (d-DMSO, 400 MHz) δ 10.47 (1H. s), 8.615 (1H,dd), 8.40 (1H, d), 7.53 (1H, dd), 7.35 (3H, m), 7.15 (2H, m), 7.05 (1H,d), 6.91 (2H, mm), 6.76 (1H, d), 6.53 (1H, dd), 6.31 (2H, d), 5.22 (2H,q), 4.34 (1H, b), 3.39 (1H, s), 2.87 (2H, d). MS (m/z) 484 [M+H]⁺.

Example 403

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4,5,6,7-tetrahydro-3-formyl-4,7-(methano)indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(403)

To a 0° C. solution of Compound 409 (200 mg, 0.34 mmol) in DME (680 ul)was added N-methylmorpholine (37 ul, 0.34 mmol) andisobutylchloroformate (45 ul, 0.34 mmol). The reaction was stirred at 0°C. for 5 min. then filtered to remove the precipitate. Washed theprecipitate 3×DME (2 ml total). To the combined filtrates was addedNaBH₄ (19.3 mg, 0.51 mmol) in H₂O. The reaction was stirred 5 min. atroom temperature. An additional 5.8 mg of NaBH₄ was added to drive thereaction to completion. The reaction mixture was partitioned betweenEtOAc and H₂O. Extracted the aqueous layer 2× EtOAc. The combinedorganics were washed with brine, dried over MgSO₄, filtered andconcentrated. The residue on purified on SiO₂ using MeOH/CH₂Cl₂ to give108 mg of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4,5,6,7-tetrahydro-3-hydroxymethyl-4,7-(methano)indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide.This material was dissolved in CH₂Cl₂ and treated with Dess-Martinperiodinane (85.8 mg, 0.20 mmol) at room temperature for 1 hr. Thereaction mixture was filtered and concentrated. The residue wasre-dissolved in EtOAc and extracted 2× H₂O and 1× brine, dried overMgSO4, filtered and concentrated. Purified 7 mg of crude by RP HPLCusing a C18 column with a gradient of 0.1%/H₂O, 0.1% TFA-acetonitrile togive 3.2 mg of the title compound. MS (m/z) 574 [M+H]⁺. The 100 mgremaining was used crude.

Example 404

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-fluoro-2-methylphenyl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(404)

Prepared 2 mg the title compound by a method analogous to 55F using(4-fluoro-2-methylphenyl)-boronic acid (15.3 mg, 0.10 mmol) and 55E(40.7 mg, 0.83 mmol). MS (m/z) 518 [M+H]⁺.

Example 405

Synthesis of(S)-2-chloro-4-(2-(2-(3,5-difluorophenyl)-1-(2-(5-fluoro-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)-N-methylbenzamide(405)

Prepared 8 mg of the title compound by a method analogous to 55F using3-chloro-4-(methylcarbamoyl)phenylboronic acid and 55E. MS (m/z) 578[M+H]⁺.

Example 406

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(3,4-difluorophenyl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(406)

Prepared 28.1 mg of the title compound by a method analogous to 55Fusing 3,4-difluorophenylboronic acid and 55E. MS (m/z) 522 [M+H]⁺.

Example 407

Synthesis of(S)—N-(1-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(407)

Prepared 1.4 mg of the title compound by a method analogous to 57B using57A and 1H-pyrrolo[2,3-b]pyridin-5-ylboronic acid. MS (m/z) 583 [M+H]⁺.

Example 408

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-(methylsulfonyl)phenyl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(408)

Prepared 24 mg of the title compound by analogous method to 55F using3-(methylsulfonyl)boronic acid and 55E. MS (m/z) 564 [M+H]⁺.

Example 409

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4,5,6,7-tetrahydro-3-carboxy-4,7-(methano)indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(409)

Prepared 209 mg of the title compound by a method analogous to 74C usingcompound 90F MS (m/z) 590 [M+H]⁺.

Example 410

Synthesis of(S)—N-(1-(3-(quinole-5-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide (410)

Prepared 19.8 mg of the title compound by a method analogous to 68Busing 68A and quinoline-5-boronic acid. MS (m/z) 608 [M+H]⁺.

Example 411

Synthesis of(S)—N-(1-(3-(quinoline-6-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(411)

Prepared 6.1 mg of the title compound by a method analogous to 68B using68A and quinoline-6-boronic acid. MS (m/z) 608 [M+H]⁺.

Example 412

Synthesis of(S)-2-chloro-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-fluoro-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(412)

Prepared 37 mg of the title compound by a method analogous to 55F using4-chloro-3-carbamoylphenyl boronic acid. ¹H NMR (400 MHz, d6-DMSO) δ10.87 (s, 1H), 8.79-8.55 (m, 2H), 7.81 (s, 1H), 7.56 (dd, 2H), 7.46-7.31(m, 3H), 7.28-7.00 (m, 4H), 6.96-6.74 (m, 3H), 6.51 (d, 2H), 5.14 (q,1H), 3.42 (s, 2H), 2.98 (d, 2H). MS (m/z) 563 [M+H]⁺.

Example 413

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-(methylsulfonyl)phenyl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(413)

Prepared 16.1 mg of the title compound by a method analogous to 55Fusing 4-(methylsulfonyl)boronic acid and 55E. MS (m/z) 564 [M+H]⁺.

Example 414

Synthesis of(S)-5-(2-(1-(2-(3-(difluoromethyl)-4,4-difluoro-7-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(414)

Prepared 6 mg of the title compound by a method analogous to 397 usingcompound 102D. MS (m/z) 652.4 [M+H]⁺.

Example 415

Synthesis of(S)—N-(1-(3-(quinoxalin-6-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(415)

Prepared 5.1 mg of the title compound by a method analogous to 68B using68A and 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline. MS(m/z) 609 [M+H]⁺.

Example 416

Synthesis of(S)—N-(1-(3-(biphenyl-4-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(416)

Prepared 27 mg of the title compound by a method analogous to 55F using4-phenyl-phenylboronic acid and 55E. MS (m/z) 562 [M+H]⁺.

Example 417 Synthesis of(S)—N-tert-butyl-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-fluoro-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(417)

Prepared 34.9 mg of the title compound by a method analogous to 55Fusing 3-(tert-butylcarbamoyl)-4-fluorophenylboronic acid and 55E. MS(m/z) 603 [M+H]⁺.

Example 418

Synthesis of (S)-3-(2-(1-(2-(IH-benzo[d]imidazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(418)

Prepared 30 mg of the title compound by a method analogous to 50D usingbenzimidazole-1-acetic acid and 50C. ¹H NMR (400 MHz, dmso) δ 9.28 (d,1H), 9.19 (s, 1H), 8.73 (dd, 1H), 8.03-7.81 (m, 2H), 7.80-7.59 (m, 3H),7.53-7.29 (m, 6H), 6.94 (t, 1H), 6.57 (d, 2H), 5.24-5.07 (m, 3H), 3.05(ddd, 2H). MS (m/z) 512 [M+H]⁺.

Example 419

Synthesis of((S)—N-(2-(3,5-difluorophenyl)-1-(6′-fluoro-5′-methyl-3,3′-bipyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(419)

Prepared 26.7 mg of the title compound by a method analogous to 55Fusing 2-Fluoro-3-methylpyridine-5-boronic acid and 55E. MS (m/z) 519[M+H]⁺.

Example 420

Synthesis of(S)—N-(1-(3-(isoquinole-5-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(420)

Prepared 17.4 mg of the title compound by a method analogous to 68Busing 68A and isoquinoline-5-boronic acid. MS (m/z) 608 [M+H]⁺.

Example 421

Synthesis of(S)—N-(1-(3-(indozol-5-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide (421)

Prepared 3 mg of the title compound by a method analogous to 68B using68A and indazole-5-boronic acid. MS (m/z) 597 [M+H]⁺.

Example 422

Synthesis of((S)—N-(1-(3-(3,5-dichlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(422)

Prepared 25.2 mg of the title compound by a method analogous to 55Fusing 3,5-dichloro-phenylboronic acid and 55E. MS (m/z) 554 [M+H]⁺.

Example 423

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-p-tolylpyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(423)

Prepared 34 mg of the title compound by a method analogous to 55F using4-methyl-phenylboronic acid and 55E. MS (m/z) 500 [M+H]⁺.

Example 424

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(3-(morpholine-4-carbonyl)phenyl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(424)

Prepared 20.9 mg of the title compound by a method analogous to 401Cusing 401B and morpholine. ¹H NMR (400 MHz, CD₃OD) δ 8.71 (d, 1H), 7.89(d, 1H), 7.72 (s, 1H), 7.62 (d, 1H), 7.52 (t, 1H), 7.40 (dd, 1H), 7.23(d, 1H), 6.68 (t, 1H), 6.26 (d, 2H), 5.52 (t, 1H), 3.66 (d, 2H), 3.01(dd, 2H), 2.89 (d, 5H), 2.55 (s, 2H), 2.42 (d, 2H), 1.76 (s, 4H). MS(m/z) 654 [M+H]⁺.

Example 435

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-(methylsulfonyl)phenyl)pyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(425)

Prepared 11.9 mg of the title compound by a method analogous to compound57B using 57A and 4-methylsulfonylphenyl boronic acid. MS (m/z) 619[M+H]⁺.

Example 426

Synthesis of(S)-3-(2-(1-(2-(1H-indol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(426)

Prepared 35 mg of the title compound by a method analogous to 50D usingindole-1-acetic acid ¹H NMR (400 MHz, dmso) δ 10.82 (s, 1H), 8.66 (dd,2H), 7.92 (d, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.61 (dd, 1H), 7.49-7.35(m, 4H), 7.26 (dd, 1H), 7.05-6.98 (m, 2H), 6.91 (t, 1H), 6.74-6.61 (m,1H), 6.49 (d, 2H), 5.17 (dd, 3H), 4.70-4.65 (m, 1H), 3.44 (q, 2H), 2.95(d, 2H). MS (m/z) 529 [M+H]⁺.

Example 427

Synthesis of(S)—N-(1-(3-(4-(N-(3-methylbutanoyl)sulfamoyl)phenyl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide (427)

Prepared 11.6 mg of the title compound by a method analogous to 68Busing 68A and 4-(N-(3-methylbutanoyl)sulfamoyl)phenylboronic acid. MS(m/z) 720 [M+H]⁺.

Example 428

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(3-sulfamoylphenyl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(428)

Prepared 43 mg of the title compound by analogous method to 55F using3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide. ¹HNMR (400 MHz, D6-DMSO) δ 10.87 (s, 9H), 8.69 (dd, J=9.5, 4.9 Hz, 19H),7.82 (d, J=7.7 Hz, 10H), 7.68 (s, 11H), 7.61-7.16 (m, 69H), 7.13-7.02(m, 19H), 6.93-6.78 (m, 22H), 6.52 (d, J=6.4 Hz, 31H), 5.13 (dd, J=14.9,7.9 Hz, 13H), 3.50-3.33 (m, 20H), 3.10-2.86 (m, 21H), 2.05 (s, 6H),1.26-0.77 (m, 19H). MS (m/z) 565 [M+H]⁺.

Example 429

Synthesis of(S)—N-(1-(3-(4-(N-methylsulfamoyl)phenyl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(429)

Prepared 17.3 mg of the title compound by a method analogous to 68Busing 68A and 4-(N-methylsulfamoyl)phenylboronic acid pinacol ester. MS(m/z) 650 [M+H]⁺.

Example 430

Synthesis of(S)—N-(1-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(430)

Prepared 26.7 mg of the title compound by analogous method to 55F using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridineand 55E. MS (m/z) 526 [M+H]⁺.

Example 431

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(431)

Prepared 38 mg of the title compound by a method analogous to 55F using3-trifluoromethoxyphenyl boronic acid and 55E. MS (m/z) 570 [M+H]⁺.

Example 432

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(6′-(pyrrolidin-1-yl)-3,3′-bipyridin-2-yl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(432)

Prepared 16.3 mg of the title compound by a method analogous to compound57B using 57A and 6-(pyrrolidin-1-yl)pyridin-3-ylboronic acid. MS (m/z)611 [M+H]⁺.

Example 433

Synthesis of(S)—N-(1-(3-(4-(methylsulfonamido)phenyl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide (433)

Prepared 20.6 mg of the title compound by a method analogous to 68Busing 68A and N-4-methanesulfonamidephenylboronic acid. MS (m/z) 650[M+H]⁺.

Example 434

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(434)

Prepared 1.5 mg of the title compound by a method analogous to 55F using3-fluoro-4-chlorophenylboronic acid and 55E. MS (m/z) 538 [M+H]⁺.

Example 435

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(6-methoxynaphthalen-2-yl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(435)

Prepared 37.1 mg of the title compound by a method analogous to 55Fusing 6-methoxy-2-naphthaleneboronic acid and 55E. MS (m/z) 566 [M+H]⁺.

Example 436

Synthesis of(S)—N-(1-(3-(isoquinolin-6-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(436)

Prepared 15.1 mg of the title compound by a method analogous to 68Busing 68A and isoquinoline-6-ylboronic acid. MS (m/z) 608 [M+H]⁺.

Example 437

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(2-(hydroxymethyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(437)

Dissolved 21.8 mg of 91B in 1 ml EtOH. Added 10 mg of 10% Pd/C. Stirredat RT under 1 atm H₂ for 72 hrs. Filtered reaction and purified filtrateby RP HPLC using a C18 column with a gradient of 0.1%/H₂O, 0.1%TFA-acetonitrile to give 10.8 mg of the title compound. MS (m/z) 578[M+H]⁺.

Example 428

Synthesis of(S)—N-(1-(3-(imidazo[1,2-a]pyridine-6-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(438)

Prepared 4.3 mg of the title compound by a method analogous to 68B using68A and imidazo[1,2-a]pyridine-6-boronic acid. MS (m/z) 597 [M+H]⁺.

Example 439

Synthesis of(S)—N-(1-(3,3′-bipyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(439)

Prepared 20.8 mg of the title compound by a method analogous to 55Fusing (pyridin-3-yl)boronic acid and 55E. MS (m/z) 487 [M+H]⁺.

Example 440

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(440)

Prepared 8.9 mg of the title compound by a method analogous to 55F using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and55E. MS (m/z) 490 [M+H]⁺.

Example 441

Synthesis of(S)—N-(1-(3-(benzo[c][1,2,5]oxadiazol-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(441)

Prepared 16 mg of the title compound by a method analogous to 55F usingbenzo[c][1,2,5]oxadiazol-5-ylboronic acid and 55E. MS (m/z) 528 [M+H]⁺.

Example 442

Synthesis of(S)—N-(1-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydro-4,5-(methano)-6,6-difluoro-cyclopenta[c]pyrazol-1(4H)-yl)acetamide(442)

Prepared 1.2 mg of the title compound by a method analogous to 68B using68A and (8-Pivaloyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)boronicacid pinacol ester. MS (m/z) 613 [M+H]⁺.

Example 443

Synthesis of 3-(4-chlorophenyl)pyrazine-2-carboxylic acid (443C)

To a solution of 3-chloropyrazine-2-carbonitrile (1.39 g, 10 mmol) in amixture of DME (30 mL) and H₂O (15 mL) was added 4-chlorophenylboronicacid (1.56 g, 10 mmol) and K₂CO₃ (4.13 g, 30 mmol), Pd(OAc)₂ (112 mg,0.5 mmol) and triphenylphosphine (polymer-bound, 3.0 mmol). The reactiontube was sealed and heated at 95° C. overnight. After cooled to roomtemperature, the reaction mixture was poured into ethyl acetate andfiltered through a pad of celite. The filtrate was concentrated todryness and dissolved in 50 mL MeOH and 80 mL 4 N NaOH. The reaction washeated at 80° C. overnight. After cooled to room temperature, themixture was acidified with concentrated HCl to pH=1. After removing thevolatile, the crude was used in the next step without furtherpurification.

Synthesis of 3-(4-chlorophenyl)-N-methoxy-N-methylpyrazine-2-carboxamide(443D)

Example 443D was prepared according to the method presented for thesynthesis of Example 13G utilizing crude of 443C and N,O-dimethylhydroxyamine hydrochloride to provide3-(4-chlorophenyl)-N-methoxy-N-methylpyrazine-2-carboxamide: MS (m/z):278.2 [M+H]⁺; ¹H NMR (400 MHz, cdcl₃) δ 8.69 (s, 1H), 8.55 (d, J=2.1 Hz,1H), 7.69 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 3.48 (s, 3H), 3.28(s, 3H).

Synthesis of 3-(4-chlorophenyl)pyrazine-2-carbaldehyde (443E)

To a solution of3-(4-chlorophenyl)-N-methoxy-N-methylpyrazine-2-carboxamide (670 mg, 2.4mmol) in THF (5 mL) was added DIBAL-H (1.0 M/toluene, 4.8 mmol) at −10°C. After stirred at −10° C. for 10 min, the reaction was poured intoethyl acetate and saturated NH₄Cl solution. The organic layer wasseparated and dried over sodium sulfate, filtered and concentrated.After removing the volatile, the crude was used in the next step withoutfurther purification. MS (m/z): 219.2 [M+H]⁺.

Synthesis ofN-((3-(4-chlorophenyl)pyrazin-2-yl)methylene)-2-methylpropane-2-sulfinamide(443F)

To a solution of 3-(4-chlorophenyl)pyrazine-2-carbaldehyde (crude fromabove reaction) in DCM (5 mL) was added(S)-2-methylpropane-2-sulfinamide (320 mg, 2.64 mmol) and CuSO₄ (766 mg,4.8 mmol) at room temperature. After stirred at room temperature for 3h, the reaction was filtered through a pad of celite and washed withDCM. The organic was dried over sodium sulfate, filtered andconcentrated. After removing the volatile, the resulting residue waspurified by silica gel chromatography eluting with EtOAc/hexanes toafford 0.48 g of the title product. MS (m/z): 321.8 [M+H]⁺.

Synthesis ofN-(1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(443G)

To a solution ofN-((3-(4-chlorophenyl)pyrazin-2-yl)methylene)-2-methylpropane-2-sulfinamide(480 mg, 1.5 mmol) and Cu(OTf) (27 mg, 0.075 mmol) in DCM (5 mL) wasadded (3,5-difluorobenzyl)magnesium bromide (0.5 M in ether, 3.0 mmol)at room temperature. After stirred at room temperature for 1 h, thereaction was poured into ethyl acetate and saturated NH₄Cl solution. Theorganic layer was separated and dried over sodium sulfate, filtered andconcentrated. After removing the volatile, the crude was used in thenext step without further purification. MS (m/z): 449.8 [M+H]⁺.

Synthesis of1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethanamine(443H)

To a solution ofN-(1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide(crude from above reaction) in MeOH (5 mL) was added 2 mL 4 N HCl indioxane at room temperature. After stirred at room temperatureovernight, the volatile was removed in vacuo and the crude was used inthe next step without further purification. MS (m/z): 346.1 [M+H]⁺.

Synthesis ofN-(1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-indol-3-yl)acetamide(443I)

Example 443I was prepared (10.3 mg) according to the method presentedfor the synthesis of Example 13G utilizing 443H and2-(5-hydroxy-1H-indol-3-yl)acetic acid to provide(S)-5-(2-(1-(2-(5-bromo-1H-indol-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide:MS (m/z): 520.0 [M+H]⁺; ¹H NMR (400 MHz, dmso) δ 10.47 (s, 1H),8.74-8.63 (m, 2H), 8.59 (s, 1H), 7.40 (s, 4H), 7.07 (d, J=8.6 Hz, 1H),6.92 (d, J=15.6 Hz, 2H), 6.78 (s, 1H), 6.55 (d, J=8.3 Hz, 1H), 6.41 (d,J=7.1 Hz, 2H), 5.25 (q, J=7.5 Hz, 1H), 3.41 (s, 2H), 3.04 (dd, J=12.9,6.9 Hz, 1H), 3.01-2.87 (m, 1H).

Example 444

Synthesisof(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-fluoro-1-(methylsulfonyl)-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(444)

To a solution of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-fluoro-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(10 mg, 0.02 mmol) in DMF (1 mL) was added NaH (1.6 mg, 0.04 mmol) andmethylsulfonyl chloride (23 mg, 0.2 mmol). The reaction was stirred atroom temperature overnight and was then purified by reverse phase HPLCeluting with acetonitrile/water to afford 1.0 mg of the title compound.MS (m/z): 625.1 [M+H]⁺; HPLC retention time 3.74 min (2-98%acetonitrile:water with 0.05% trifluoroacetic acid).

Example 445

Synthesis of(S)-5-(2-(1-(2-(5-bromo-1H-indol-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(445)

Example 445 was prepared (5.7 mg) according to the method presented forthe synthesis of Example 13G utilizing 54B and2-(5-bromo-1H-indol-3-yl)acetic acid to provide(S)-5-(2-(1-(2-(5-bromo-1H-indol-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide:MS (m/z): 607.2 [M+H]⁺; HPLC retention time 3.62 min (2-98%acetonitrile:water with 0.05% trifluoroacetic acid). ¹H NMR (400 MHz,cdcl₃) δ 8.51 (d, J=7.4 Hz, 1H), 8.40 (d, J=5.5 Hz, 1H), 8.26 (s, 1H),7.90 (t, J=29.1 Hz, 1H), 7.81 (s, 1H), 7.61 (dd, J=17.6, 9.9 Hz, 2H),7.34-7.21 (m, 1H), 7.21-7.06 (m, 3H), 6.93 (d, J=8.6 Hz, 1H), 6.49 (t,J=7.7 Hz, 2H), 6.11 (d, J=5.9 Hz, 2H), 5.33 (q, J=7.9 Hz, 1H), 3.65 (dd,J=22.0, 14.7 Hz, 1H), 3.53 (d, J=15.8 Hz, 1H), 3.03 (dd, J=13.6, 7.7 Hz,1H), 2.96-2.82 (m, 1H).

Example 446

Synthesisof(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(446)

A solution of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3′-(trifluoromethyl)-6′,7′-dihydrospiro[[1,3]dioxolane-2,5′-indazole]-1′(4′H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(320 mg, 0.48 mmol) in 3 mL DCM and 1 mL TFA was stirred at roomtemperature overnight. The volatile was removed in vacuo and the residuewas then purified by reverse phase HPLC eluting with acetonitrile/waterto afford 11.8 mg of the title compound: MS (m/z): 616.7 [M+H]⁺; HPLCretention time 0.94 min (2-98% acetonitrile:water with 0.05%trifluoroacetic acid). ¹H NMR (400 MHz, cd₃od) δ 8.76-8.67 (m, 1H), 7.68(dd, J=7.8, 1.6 Hz, 1H), 7.57-7.46 (m, 2H), 7.32 (s, 1H), 7.22 (m, 1H),6.68 (t, J=9.2 Hz, 1H), 6.34 (d, J=6.2 Hz, 2H), 5.36 (t, J=7.6 Hz, 1H),4.93-4.76 (m, 2H), 3.29 (dt, J=3.2, 1.6 Hz, 1H), 3.06 (d, J=7.5 Hz, 1H),2.85 (d, J=46.2 Hz, 2H), 2.77-2.62 (m, 2H), 2.60-2.42 (m, 2H), 1.98 (dt,J=31.8, 11.5 Hz, 2H).

Example 447

Synthesis ofN-(1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(1H-indazol-3-yl)acetamide(447)

Example 447 was prepared (5.4 mg) according to the method presented forthe synthesis of Example 13G utilizing 443H and2-(1H-indazol-3-yl)acetic acid to provideN-(1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(1H-indazol-3-yl)acetamide:MS (m/z): 505.1 [M+H]⁺; ¹H NMR (400 MHz, dmso) δ 9.06 (d, J=7.4 Hz, 1H),8.75 (s, 1H), 8.62 (s, 1H), 7.50-7.36 (m, 5H), 7.26 (t, J=7.6 Hz, 1H),6.99 (dt, J=14.9, 7.8 Hz, 3H), 6.51 (d, J=6.9 Hz, 2H), 5.26 (d, J=7.2Hz, 1H), 3.83-3.68 (m, 2H), 3.15-2.93 (m, 2H).

Example 448

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(448)

To solution of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(24 mg, 0.04 mmol) in 1 mL DCM was added NaBH₄ (200 mg, 5.3 mmol) andthe resulting solution was stirred at room temperature overnight. Thereaction was poured into ethyl acetate and washed with saturated NH₄Clsolution and brine. The organic layer was dried over sodium sulfate,filtered and concentrated. The resulting residue was purified by reversephase HPLC eluting with acetonitrile/water to afford 10.8 mg of thetitle compound: MS (m/z): 618.3 [M+H]⁺; ¹H NMR of mixture ofdiastereomers (400 MHz, cdcl₃) δ 9.31 (d, J=7.3 Hz, 1H), 8.75 (s, 1H),7.99-7.88 (m, 1H), 7.80-7.58 (m, 2H), 7.50 (s, 1H), 7.34-7.22 (m, 1H),6.98 (m, 1H), 6.61 (t, J=8.6 Hz, 1H), 6.45 (s, 1H), 6.21 (s, 2H),5.57-5.40 (m, 1H), 4.89-4.61 (m, 2H), 3.15 (dd, J=13.5, 7.0 Hz, 1H),3.10-2.95 (m, 1H), 2.88 (d, J=12.2 Hz, 1H), 2.70 (m, 2H), 2.55 (dd,J=38.9, 32.9 Hz, 1H), 2.01 (m, 1H), 1.91 (m, 1H).

Example 449 and 450

Synthesis of 5-(2-((1S)-1-(2-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(449) and5-(2-((1S)-1-(2-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(450)

The two diastereomers of 181E were separated by chiral HPLC (ChiralpakAD-H, Heptane:IPA 70:30) to provide 449 (18 mg, fast eluting peak) and450 (18 mg, slow eluting peak). MS (m/z): 636.4 [M+H]⁺.

Example 451

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(451B)

Example 451B was prepared (6.6 mg) according to the method presented forthe synthesis of Example 58D utilizing 56A and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazoleto provide(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide:MS (m/z): 674.1 [M+H]⁺; ¹H NMR (400 MHz, cdcl₃) δ 8.57 (d, J=4.9 Hz,1H), 7.79 (s, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H),7.38-7.22 (m, 1H), 7.21-7.11 (m, 1H), 6.78 (s, 1H), 6.53 (t, J=9.0 Hz,1H), 6.09 (d, J=6.0 Hz, 2H), 5.82 (s, 1H), 5.42 (dd, J=14.3, 8.4 Hz,1H), 4.83 (s, 2H), 2.95-2.72 (m, 2H), 1.35-1.20 (m, 12H).

Example 452 and 453

Synthesis of methyl 4,6-dihydro-1H-furo[3,4-c]pyrazole-3-carboxylate(452B)

Example 452B was prepared according to the method presented for thesynthesis of Example 55C utilizing4,6-dihydro-1H-furo[3,4-c]pyrazole-3-carboxylic acid to provide thetitle compound: MS (m/z): 169.1 [M+H]⁺.

Synthesis of (S)-methyl1-(2-((1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)amino)-2-oxoethyl)-4,6-dihydro-1H-furo[3,4-c]pyrazole-3-carboxylate(452C) and (S)-methyl2-(2-((1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)amino)-2-oxoethyl)-4,6-dihydro-2H-furo[3,4-c]pyrazole-3-carboxylate(453)

Example 452C (2.4 mg) and 453 (2.7 mg) were prepared according to themethod presented for the synthesis of Example 58D utilizing 56A andmethyl 4,6-dihydro-1H-furo[3,4-c]pyrazole-3-carboxylate to provide(S)-methyl1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-4,6-dihydro-1H-furo[3,4-c]pyrazole-3-carboxylate:MS (m/z): 580.4 [M+H]⁺; ¹H NMR (400 MHz, cdcl₃) δ 9.58 (s, 1H), 8.78 (d,J=4.8 Hz, 1H), 7.93 (d, J=6.7 Hz, 1H), 7.79-7.62 (m, 2H), 7.58 (s, 1H),7.33-7.22 (m, 2H), 6.86 (s, 1H), 6.61 (s, 1H), 6.35 (s, 1H), 6.18 (d,J=5.9 Hz, 2H), 5.46 (s, 1H), 5.00 (s, 2H), 4.92-4.69 (m, 4H), 3.87 (s,3H), 3.07-2.80 (m, 1H), 3.07-2.81 (m, 1H) and (S)-methyl2-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-4,6-dihydro-2H-furo[3,4-c]pyrazole-3-carboxylate:MS (m/z): 580.7 [M+H]⁺.

Example 454

Synthesis ofN-(1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide(454)

Example 454 was prepared (4.2 mg) according to the method presented forthe synthesis of Example 13G utilizing 443H and2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetic acid to provideN-(1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide:MS (m/z): 535.1 [M+H]⁺; ¹H NMR (400 MHz, dmso) δ 11.08 (s, 1H), 8.68 (d,J=8.2 Hz, 2H), 8.62 (s, 1H), 7.73 (s, 1H), 7.50-7.39 (m, 4H), 7.28 (s,1H), 6.91 (t, J=9.1 Hz, 1H), 6.59 (d, J=8.8 Hz, 1H), 6.38 (d, J=6.6 Hz,2H), 5.32 (d, J=7.5 Hz, 1H), 3.86 (s, 3H), 3.58-3.31 (m, 2H), 2.97 (m,2H).

Example 455

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(455)

Example 455 was prepared (55 mg) according to the method presented forthe synthesis of Example 13G utilizing 54B and2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid to provide(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide:MS (m/z): 548.1 [M+H]⁺; HPLC retention time 3.56 min (2-98%acetonitrile:water with 0.05% trifluoroacetic acid). ¹H NMR (400 MHz,cdcl₃) δ 9.53 (d, J=7.1 Hz, 1H), 8.79 (d, J=5.5 Hz, 1H), 7.98 (d, J=7.9Hz, 1H), 7.93-7.70 (m, 2H), 7.62 (s, 1H), 7.60 (d, J=6.5 Hz, 1H),7.62-7.23 (m, 2H), 6.95 (d, J=10.2 Hz, 1H), 6.61 (dd, J=19.8, 11.5 Hz,3H), 6.20 (d, J=6.1 Hz, 2H), 5.48 (q, J=7.6 Hz, 1H), 5.00-4.84 (m, 2H),3.18 (dd, J=13.5, 6.8 Hz, 1H), 3.02 (dd, J=13.6, 9.0 Hz, 1H).

Example 456

Synthesis of(S)-1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-4,6-dihydro-1H-furo[3,4-c]pyrazole-3-carboxylicacid (456)

The carboxylic acid 456 was prepared (4.6 mg) according to the methodpresented for the synthesis of Example 60G utilizing 452C as startingmaterial to provide(S)-1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-4,6-dihydro-1H-furo[3,4-c]pyrazole-3-carboxylicacid: MS (m/z): 566.3 [M+H]⁺. ¹H NMR (400 MHz, cdcl₃) δ 8.83 (d, J=4.0Hz, 1H), 7.88 (d, J=6.9 Hz, 1H), 7.66 (dd, J=21.3, 15.7 Hz, 1H),7.60-7.58 (m, 1H), 7.24 (m, 2H), 6.98 (m, 1H), 6.68 (s, 1H), 6.57 (s,1H), 6.16 (d, J=5.7 Hz, 3H), 5.45 (s, 1H), 5.25 (d, J=4.3 Hz, 2H), 4.97(s, 2H), 4.85 (s, 2H), 3.13 (d, J=46.3 Hz, 1H), 3.05 (m, 1H).

Example 457

Synthesis of 5-(2-((IS)-2-(3,5-difluorophenyl)-1-(2-(4-hydroxy-3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(457)

The example 457 was prepared (2.6 mg) according to the method presentedfor the synthesis of Example 448 utilizing 465 as starting material: MS(m/z): 616.1 [M+H]⁺.

Example 458

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-5,6,7,8-tetrahydrocyclohepta[c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(458)

Example 458 was prepared (22 mg) according to the method presented forthe synthesis of Example 13G utilizing 54B and2-(3-(trifluoromethyl)-5,6,7,8-tetrahydrocyclohepta[c]pyrazol-1(4H)-yl)aceticacid to provide(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-5,6,7,8-tetrahydrocyclohepta[c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide:MS (m/z): 616.6 [M+H]⁺; HPLC retention time 1.31 min (2-98%acetonitrile:water with 0.05% trifluoroacetic acid). ¹H NMR (400 MHz,cdcl₃) δ 9.37 (d, J=7.5 Hz, 1H), 8.79-8.70 (m, 1H), 7.96-7.90 (m, 1H),7.90-7.32 (m, 3H), 7.33-7.22 (m, 1H), 6.96 (d, J=10.7 Hz, 1H), 6.61 (t,J=5.6 Hz, 2H), 6.19 (d, J=5.7 Hz, 2H), 5.47 (dd, J=16.0, 7.5 Hz, 1H),4.92-4.70 (m, 2H), 3.15 (dd, J=13.5, 6.9 Hz, 1H), 3.06-2.91 (m, 1H),2.91-2.86 (m, 1H), 2.69-2.40 (m, 4H), 1.80 (d, J=5.1 Hz, 2H), 1.71-1.43(m, 4H), 1.39 (dd, J=13.0, 6.7 Hz, 1H).

Example 459

Synthesis ofN-(1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(459)

Example 459 was prepared (11.3 mg) according to the method presented forthe synthesis of Example 13G utilizing 443H and2-(5-fluoro-1H-indol-3-yl)acetic acid to provideN-(1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide:MS (m/z): 522.2 [M+H]⁺; ¹H NMR (400 MHz, dmso) δ 10.89 (s, 1H), 8.84 (d,J=7.8 Hz, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 7.43 (s, 4H), 7.26 (dd,J=8.9, 4.5 Hz, 1H), 7.13 (d, J=10.9 Hz, 2H), 6.88 (dt, J=17.2, 9.0 Hz,2H), 6.47 (d, J=7.2 Hz, 2H), 5.25 (d, J=7.6 Hz, 1H), 3.46 (s, 2H),3.13-2.90 (m, 2H).

Example 460

Synthesis of(S)-5-(2-(1-(2-(4-cyclohexenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(460)

Example 460 was prepared (4.9 mg) according to the method presented forthe synthesis of Example 55F utilizing 451B and cyclohexenyltrifluoromethanesulfonate to provide(S)-5-(2-(1-(2-(4-cyclohexenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide:MS (m/z): 628.3 [M+H]⁺; HPLC retention time 1.26 min (2-98%acetonitrile:water with 0.05% trifluoroacetic acid). ¹H NMR (400 MHz,cdcl₃) δ 9.25 (s, 1H), 8.77 (s, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.80 (m,2H), 7.51 (d, J=10.6 Hz, 1H), 7.41-7.22 (m, 2H), 6.93 (s, 1H), 6.66-6.63(m, 1H), 6.59 (d, J=22.3 Hz, 1H), 6.18 (d, J=5.4 Hz, 2H), 5.88 (s, 1H),5.51 (s, 1H), 4.88 (d, J=9.5 Hz, 2H), 3.22 (m, 1H), 3.14 (m, 1H), 2.16(m, 4H), 1.73-1.58 (m, 4H).

Example 461

Synthesis of5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(461)

Example 461 was prepared (24 mg) according to the method presented forthe synthesis of Example 58D utilizing 56A and 58B to provide(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide:MS (m/z): 576.2 [M+H]⁺; ¹H NMR (400 MHz, cdcl₃) δ 9.39 (d, J=7.6 Hz,1H), 8.76 (d, J=5.4 Hz, 1H), 7.88 (m, 1H), 7.79 (s, 1H), 7.84-7.57 (m,2H), 7.29 (d, J=8.5 Hz, 1H), 7.27-7.21 (m, 1H), 6.95 (d, J=9.6 Hz, 1H),6.67-6.38 (m, 2H), 6.33 (s, 1H), 6.19 (d, J=5.8 Hz, 2H), 5.48 (dd,J=16.2, 7.6 Hz, 1H), 4.82 (q, J=16.7 Hz, 2H), 3.23-3.02 (m, 1H),3.02-2.78 (m, 1H), 2.50 (dd, J=14.9, 7.5 Hz, 2H), 1.23 (t, J=7.5 Hz,3H).

Example 462

Synthesis of bicyclo[3.1.0]hexan-2-one (462B)

To a solution of trimethylsulfoxonium iodide (12.1 g, 55 mmol) in DMSO(50 mL) was added NaH (2.2 g, 55 mmol) in an ice-water bath. Thesolution was stirred at room temperature for 10 min and thencyclopent-2-enone (4.1 g, 50 mmol) was added. The reaction was stirredat room temperature for 1 h and was then poured into ether. The organicwas washed with 5% LiCl and dried over sodium sulfate, filtered andconcentrated. The resulting residue was purified by silica gelchromatography eluting with EtOAc/hexanes to afford 2.5 g of the titleproduct. Rf=0.15 (9:1 hexanes: EtOAc).

Synthesis of 3-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexan-2-one (462C)

Example 462C was prepared according to the method presented for thesynthesis of Example 60B utilizing bicyclo[3.1.0]hexan-2-one andtrifluoroethyl acetate to provide3-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexan-2-one as a red oil: MS(m/z): 196.0 [M+H]⁺.

Synthesis of3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazole(462D)

Example 462D was prepared according to the method presented for thesynthesis of Example 58B utilizing3-(2,2,2-trifluoroacetyl)bicyclo[3.1.0]hexan-2-one and hydrazine hydrateto provide the title compound: MS (m/z): 189.1 [M+H]⁺.

Synthesis of ethyl2-(3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-1-yl)acetate(462E)

Example 462E was prepared according to the method presented for thesynthesis of Example 58D utilizing 462D and ethyl 2-bromoacetate toprovide the title compound: MS (m/z): 275.1 [M+H]⁺.

Synthesis of ethyl2-(4-oxo-3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-1-yl)acetate(462F)

Example 462F was prepared according to the method presented for thesynthesis of Example 60D utilizing 462E to provide the title compound:MS (m/z): 275.1 [M+H]⁺.

Synthesis of ethyl2-(3-(trifluoromethyl)-5,5a-dihydrospiro[cyclopropa[4,5]cyclopenta[1,2-c]pyrazole-4,2′-[1,3]dithiolan]-1(4aH)-yl)acetate(462G)

Example 462G was prepared according to the method presented for thesynthesis of Example 60E utilizing 462F to provide the title compound:MS (m/z): 364.1 [M+H]⁺.

Synthesis of ethyl2-(4,4-difluoro-3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-1-yl)acetate(462H)

Example 462H was prepared according to the method presented for thesynthesis of Example 60F utilizing 462G to provide the title compound:MS (m/z): 311.2 [M+H]⁺.

Synthesis of2-(4,4-difluoro-3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (462I)

Example 462I was prepared according to the method presented for thesynthesis of Example 60G utilizing 462H to provide the title compound:MS (m/z): 283.0 [M+H]⁺.

Synthesis of5-(2-((1S)-1-(2-(4,4-difluoro-3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(462J)

Example 462J was prepared (7.9 mg) according to the method presented forthe synthesis of Example 13G utilizing 462I and 54B to provide the titlecompound: MS (m/z): 636.4 [M+H]⁺. ¹H NMR of the mixture of diastereomers(400 MHz, cdcl₃) δ 10.07 (d, J=7.2 Hz, 1H), 9.93 (d, J=6.6 Hz, 1H), 8.78(d, J=5.4 Hz, 2H), 8.02 (d, J=4.6 Hz, 2H), 7.74 (dd, J=45.4, 39.5 Hz,4H), 7.60 (m, 2H), 7.32 (t, J=9.8 Hz, 2H), 6.94 (s, 2H), 6.80-6.60 (m,4H), 6.15 (dd, J=50.7, 43.2 Hz, 4H), 5.49 (dd, J=15.6, 7.5 Hz, 2H),4.95-4.72 (m, 4H), 3.31-3.13 (m, 2H), 3.13-2.94 (m, 2H), 2.63 (m, 2H),2.36 (m, 2H), 1.37 (dd, J=14.2, 7.3 Hz, 2H), 1.25 (s, 2H).

Example 463

Synthesis of(S)-5-(2-(1-(2-(4-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(463)

Example 463 was prepared (5.2 mg) according to the method presented forthe synthesis of Example 58D utilizing 56A and4-bromo-3-(trifluoromethyl)-1H-pyrazole to provide(S)-5-(2-(1-(2-(4-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide:MS (m/z): 626.6 [M+H]⁺; ¹H NMR (400 MHz, cdcl₃) δ 8.58 (d, J=4.7 Hz,1H), 7.61 (d, J=10.6 Hz, 2H), 7.50 (d, J=7.6 Hz, 1H), 7.41 (s, 1H),7.39-7.13 (m, 3H), 6.77 (s, 1H), 6.55 (t, J=8.7 Hz, 1H), 6.11 (d, J=6.3Hz, 2H), 5.84 (s, 1H), 5.43 (dd, J=14.6, 7.9 Hz, 1H), 4.82 (s, 2H), 2.88(dd, J=16.9, 9.0 Hz, 2H).

Example 464

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-(methylsulfonyl)-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(464)

A solution of(S)-5-(2-(1-(2-(5-bromo-1H-indol-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(30 mg, 0.04 mmol), CuI (33 mg, 0.17 mmol) and sodium methanesulfinate(17 mg, 0.17 mmol) in DMSO (1.5 mL) was subjected to microwave heatingat 150° C. for 30 min. The reaction mixture was purified by reversephase HPLC eluting with acetonitrile/water to afford 2.7 mg of the titlecompound: MS (m/z): 607.3 [M+H]; ¹H NMR (400 MHz, cdcl₃) δ 9.00 (s, 1H),8.52 (s, 1H), 8.39 (d, J=5.3 Hz, 1H), 8.04-7.89 (m, 2H), 7.65 (dd,J=27.6, 8.5 Hz, 2H), 7.50 (d, J=8.6 Hz, 1H), 7.38-7.23 (m, 1H), 6.92 (m,1H), 6.58 (m, 1H), 6.28 (d, J=5.9 Hz, 1H), 6.08 (s, 1H), 5.42 (d, J=7.9Hz, 1H), 3.81 (d, J=15.7 Hz, 1H), 3.66 (d, J=15.7 Hz, 1H), 3.22-3.05 (m,1H), 3.02 (s, 3H), 2.99-2.96 (m, 1H).

Example 465

Synthesis of2-(4-oxo-3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (465A)

Example 465A was prepared according to the method presented for thesynthesis of Example 60G utilizing 462F to provide the title compound:MS (m/z): 259.0 [M−H]⁻.

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(4-oxo-3-(trifluoromethyl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(465B)

Example 465B was prepared (18.7 mg) according to the method presentedfor the synthesis of Example 13G utilizing 465A and 54B to provide thetitle compound: MS (m/z): 614.4 [M+H]⁺. ¹H NMR of the mixture ofdiastereomers (400 MHz, cdcl₃) δ 10.21 (d, J=7.2 Hz, 1H), 10.06 (d,J=7.0 Hz, 1H), 8.79 (d, J=5.4 Hz, 2H), 8.11-8.00 (m, 2H), 7.90-7.77 (m,4H), 7.63 (m, 2H), 7.32 (t, J=9.9 Hz, 2H), 6.94-6.67 (m, 4H), 6.63 (t,J=9.0 Hz, 2H), 6.24 (m, 4H), 5.51 (dd, J=14.8, 7.2 Hz, 2H), 5.01-4.79(m, 4H), 3.32-3.15 (m, 2H), 3.15-2.97 (m, 2H), 2.75-2.69 (m, 2H), 2.61(d, J=4.4 Hz, 2H), 1.85-1.57 (m, 4H).

Example 466 and 467

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(466) and (467)

Compound 448 was synthesized as a mixture of two diastereomers.Separation of 448 by chiral HPLC (Chiralpak IA, Heptane:Ethanol 80:20)provided 466 (5 mg, fast eluting peak, MS (m/z): 636.4 [M+H]⁺) and 467(7 mg, slow eluting peak, MS (m/z): 636.4 [M+H]⁺).

Example 468

Synthesis of ethyl2-(3′-(trifluoromethyl)-6′,7′-dihydrospiro[[1,3]dioxolane-2,5′-indazole]-1′(4′H)-yl)acetate(468B)

To a solution of3′-(trifluoromethyl)-1,4′,6′,7′-tetrahydrospiro[[1,3]dioxolane-2,5′-indazole](5.0 g, 20 mmol) in DMF (100 mL) was added NaH (528 mg, 22 mmol) andethyl 2-bromoacetate (4.0 g, 24 mmol). The reaction was stirred at 80°C. for 2 h and was then poured into ethyl acetate and washed withsaturated NH₄Cl solution and brine. The organic layer was dried oversodium sulfate, filtered and concentrated. MS (m/z): 335.2 [M+H]⁺; HPLCretention time 2.56 min (2-98% acetonitrile:water with 0.05%trifluoroacetic acid).

Synthesis of2-(3′-(trifluoromethyl)-6′,7′-dihydrospiro[[1,3]dioxolane-2,5′-indazole]-1′(4′H)-yl)aceticacid (468C)

The carboxylic acid 468C was prepared according to the method presentedfor the synthesis of Example 60G utilizing ethyl2-(3′-(trifluoromethyl)-6′,7′-dihydrospiro[[1,3]dioxolane-2,5′-indazole]-1′(4′H)-yl)acetateto provide2-(3′-(trifluoromethyl)-6′,7′-dihydrospiro[[1,3]dioxolane-2,5′-indazole]-1′(4′H)-yl)aceticacid: MS (m/z): 306.8 [M+H]⁺; HPLC retention time 2.20 min (2-98%acetonitrile:water with 0.05% trifluoroacetic acid).

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3′-(trifluoromethyl)-6′,7′-dihydrospiro[[1,3]dioxolane-2,5′-indazole]-1′(4′H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(468D)

Example 468D was prepared (5.7 mg) according to the method presented forthe synthesis of Example 13G utilizing 54B and2-(3′-(trifluoromethyl)-6′,7′-dihydrospiro[[1,3]dioxolane-2,5′-indazole]-1′(4′H)-yl)aceticacid to provide the title compound: MS (m/z): 660.3 [M+H]⁺; HPLCretention time 1.06 min (2-98% acetonitrile:water with 0.05%trifluoroacetic acid). ¹H NMR (400 MHz, cd₃od) δ 8.68 (d, J=3.0 Hz, 1H),7.56 (dd, J=7.8, 1.6 Hz, 1H), 7.46-7.33 (m, 2H), 7.28 (s, 1H), 7.23 (dd,J=24.0, 13.5 Hz, 1H), 6.65 (d, J=9.1 Hz, 1H), 6.33 (d, J=6.3 Hz, 2H),5.41-5.31 (m, 1H), 4.85-4.76 (m, 2H), 3.99 (s, 4H), 3.35-3.25 (m, 2H),3.05 (dt, J=19.7, 13.0 Hz, 2H), 2.82-2.68 (m, 2H), 2.63 (d, J=6.8 Hz,1H), 1.92 (dd, J=14.2, 7.5 Hz, 3H).

Example 469

Synthesis of5-(2-(1-(2-(1H-indazol-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(469)

Example 469 was prepared (21.5 mg) according to the method presented forthe synthesis of Example 13G utilizing 54B and 2-(1H-indazol-3-yl)aceticacid to provide the title compound: MS (m/z): 530.5 [M+H]⁺; ¹H NMR (400MHz, dmso) δ 8.91 (d, J=8.0 Hz, 1H), 8.70 (d, J=4.8 Hz, 1H), 7.62 (dd,J=18.7, 9.7 Hz, 3H), 7.48 (d, J=6.5 Hz, 1H), 7.45-7.35 (m, 4H), 7.25(dd, J=15.4, 8.1 Hz, 2H), 6.93 (dd, J=14.6, 7.5 Hz, 2H), 6.57 (d, J=6.7Hz, 2H), 5.15 (t, J=7.7 Hz, 1H), 3.78-3.64 (m, 2H), 3.02 (m, 2H).

Example 470

Synthesis of(S)—N-(1-(3-(3-amino-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(470)

To a solutionof(S)—N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(900 mg, 1.8 mmol) in a mixture of DME (6 mL) and H₂O (3 mL) was added3-amino-4-fluorophenylboronic acid (370 mg, 2.4 mmol) and K₂CO₃ (552 mg,4.0 mmol) and tetrakis triphenylphosphine palladium (115 mg, 0.1 mmol).The reaction tube was sealed and heated in a microwave reactor at 120°C. for 30 min. The reaction mixture was poured into ethyl acetate andwashed with saturated NH₄Cl solution. The organic layer was dried oversodium sulfate, filtered and concentrated. The resulting residue waspurified by silica gel chromatography eluting with EtOAc/hexanes toafford 630 mg of the title product. MS (m/z): 519.1 [M+H]⁺; HPLCretention time 3.85 min (2-98% acetonitrile:water with 0.05%trifluoroacetic acid). ¹H NMR (400 MHz, cdcl₃) δ 8.40 (s, 1H), 8.15 (s,1H), 7.52 (s, 1H), 7.33-7.07 (m, 4H), 7.05-6.86 (m, 2H), 6.48 (dd,J=36.6, 27.7 Hz, 3H), 6.37 (s, 1H), 6.12 (d, J=7.2 Hz, 2H), 5.62 (q,J=7.6 Hz, 1H), 3.81 (m, 1H), 3.67 (s, 2H), 2.86 (m, 1H).

Example 471

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(471)

Example 471 was prepared (21 mg) according to the method presented forthe synthesis of Example 58D utilizing 56A and4,5,6,7-tetrahydro-1H-indazole to provide the title compound: MS (m/z):534.0 [M+H]⁺; ¹H NMR (400 MHz, cdcl₃) 9.51 (s, 1H), 8.79 (d, J=5.3 Hz,1H), 7.94 (d, J=7.8 Hz, 1H), 7.68 (dd, J=28.6, 21.9 Hz, 1H), 7.59-7.53(m, 1H), 7.53-7.19 (m, 2H), 6.97 (s, 1H), 6.61 (s, 1H), 6.22 (dd,J=13.2, 6.5 Hz, 2H), 5.46 (d, J=6.8 Hz, 1H), 4.98 (ddd, J=41.3, 20.7,13.7 Hz, 2H), 3.18 (dd, J=12.9, 6.9 Hz, 1H), 3.11-2.95 (m, 1H), 2.71 (t,J=6.2 Hz, 1H), 2.52 (d, J=14.9 Hz, 3H), 1.83 (m, 2H), 1.77 (m, 2H).

Example 472

Synthesis of ethyl4-bromo-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate(472B)

To a solution of ethyl4-bromo-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (2.0 g, 7.0 mmol)in DMF (10 mL) was added K₂CO₃ (1.2 g, 8.4 mmol) and1-(chloromethyl)-4-methoxybenzene (1.2 g, 7.7 mmol). The reaction wasstirred at room temperature overnight and was then poured into ethylacetate and washed with saturated NH₄Cl solution and brine. The organiclayer was dried over sodium sulfate, filtered and concentrated. Theresulting residue was purified by silica gel chromatography eluting withEtOAc/hexanes to afford 2.5 g of the title product. MS (m/z): 406.6[M+H]⁺; HPLC retention time 1.60 min (2-98% acetonitrile:water with0.05% trifluoroacetic acid).

Synthesis of ethyl4-(1-fluorovinyl)-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate(472C)

To a solution of ethyl4-bromo-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate(460 mg, 1.13 mmol) in DMF (6 mL) was addedtributyl(1-fluorovinyl)stannane (492 mg, 1.4 mmol) and tetrakistriphenylphosphine palladium (130 mg, 0.12 mmol). The reaction wasdegassed with argon and heated at 100° C. overnight. The mixture wascooled to room temperature and then filtered through a pad of celite.The filtrate was diluted with ethyl acetate and washed with 5% LiClsolution and brine. The organic layer was dried over sodium sulfate,filtered and concentrated. The resulting residue was purified by silicagel chromatography eluting with EtOAc/hexanes to afford 400 mg of thetitle product. MS (m/z): 373.3 [M+H]⁺; HPLC retention time 1.61 min(2-98% acetonitrile:water with 0.05% trifluoroacetic acid).

Synthesis of4-(1-fluorovinyl)-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (472D)

The carboxylic acid 472D was prepared according to the method presentedfor the synthesis of Example 60G utilizing ethyl4-(1-fluorovinyl)-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylateto provide4-(1-fluorovinyl)-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid: MS (m/z): 342.8 [M−H]⁻; HPLC retention time 1.30 min (2-98%acetonitrile:water with 0.05% trifluoroacetic acid).

Synthesis of2-diazo-1-(4-(1-fluorovinyl)-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)ethanone(472E)

To a solution of4-(1-fluorovinyl)-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (34 mg, 0.1 mmol) in dichloroethane (1 mL) was added DMF (0.01 mL)and oxalyl chloride (25 mg, 0.2 mmol). The reaction was stirred at roomtemperature for 30 min. After removing the volatiles in vacuo, theresidue was dissolved in 1 mL dichloroethane. This solution was added toa suspension of isocyanoiminotriphenylphosphorane (45 mg, 0.15 mmol) in1 mL dichloroethane. The reaction was stirred at room temperature for 1h and water (0.5 mL) was added. The mixture was stirred overnight. Thereaction was diluted with dichloromethane and washed with brine. Theorganic layer was dried over sodium sulfate, filtered and concentrated.The resulting residue was purified by silica gel chromatography elutingwith EtOAc/hexanes to afford 30 mg of(E)-2-(4-(1-fluorovinyl)-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-oxoacetohydrazonoylchloride: MS (m/z): 405.3 [M+H]⁺; HPLC retention time 1.40 min (2-98%acetonitrile:water with 0.05% trifluoroacetic acid). The product fromthe previous step was dissolved in 1 mL dichloroethane. To this solutionwas added diisopropylamine (10 mg, 0.096 mmol) and ZnBr₂ (3.3 mg, 0.015mmol). The resulting solution was stirred at room temperature for 3days. After removing the volatile in vacuo, the resulting residue waspurified by reverse phase HPLC eluting with acetonitrile/water to afford10 mg of the title compound: MS (m/z): 369.0 [M+H]⁺.

Synthesis of3b-fluoro-1-(4-methoxybenzyl)-3-(trifluoromethyl)-4,4a-dihydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-5(3bH)-one(472F)

To a solution of2-diazo-1-(4-(1-fluorovinyl)-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)ethanone(10 mg, 0.028 mmol) in dichloroethane (1 mL) was added Cu(OTf) (10 mg,0.034 mmol). The reaction was stirred at room temperature for 3 h. Afterremoving the volatile in vacuo, the resulting residue was purified byreverse phase HPLC eluting with acetonitrile/water to afford 5 mg of thetitle compound: MS (m/z): 341.0 [M+H]⁺.

Synthesis of3b-fluoro-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1,3b,4,4a-tetrahydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2′-[1,3]dithiolane](472G)

Example 472G was prepared according to the method presented for thesynthesis of Example 60E utilizing 472F to provide the title compound:MS (m/z): 417.1 [M+H]⁺.

Synthesis of3b-fluoro-1-(4-methoxybenzyl)-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole(472H)

To a solution of 472G (40 mg, 0.096 mmol) in ethanol (2 mL) was addedRaney Nickel (1 mL slurry). The reaction was stirred at room temperaturefor 5 min. The insoluble solid were removed by filtration through a padof celite. After removing the volatile in vacuo, the resulting residuewas purified by reverse phase HPLC eluting with acetonitrile/water toafford the title compound: MS (m/z): 327.0 [M+H]⁺.

Synthesis of3b-fluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole(472I)

The solution of 472H (20 mg, 0.06 mmol) in TFA (1 mL) was subjected tomicrowave heating at 150° C. for 10 min. After removing the volatile invacuo, the resulting crude was used in the next step without furtherpurification: MS (m/z): 207.1 [M+H]⁺.

Synthesis of5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(3b-fluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(472J)

Example 472J was prepared (1.0 mg) according to the method presented forthe synthesis of Example 13G utilizing 472I and 54B to provide the titlecompound: MS (m/z): 618.1 [M+H]^(t). ¹H NMR of the mixture ofdiastereomers (400 MHz, cdcl₃) δ 9.45 (m, 1H), 9.30 (m, 1H), 8.74 (d,J=4.1 Hz, 2H), 7.93 (s, 2H), 7.72 (s, 2H), 7.59 (s, 2H), 7.24 (m, 4H),6.89 (s, 2H), 6.61 (s, 2H), 6.33 (s, 2H), 6.19 (s, 4H), 5.48 (s, 2H),4.82-4.56 (m, 4H), 3.14 (m, 2H), 3.04 (m, 2H), 2.47 (m, 6H), 1.77 (m,2H), 0.84 (m, 2H).

Example 473

Synthesis of(S)—N-(1-(3-(3-acetamido-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(473)

To a solutionof(S)—N-(1-(3-(3-amino-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(10 mg, 0.02 mmol) in DMF (1 mL) was added acetyl chloride (2.4 mg, 0.03mmol) and DIEA (3.9 mg, 0.03 mmol). The reaction was stirred at roomtemperature for 30 min. The reaction mixture was then purified byreverse phase HPLC eluting with acetonitrile/water to afford 6.7 mg ofthe title compound. MS (m/z): 561.0 [M+H]⁺; HPLC retention time 3.64 min(2-98% acetonitrile:water with 0.05% trifluoroacetic acid). ¹H NMR (400MHz, cdcl₃) δ 8.58 (d, J=5.3 Hz, 1H), 8.24 (d, J=31.7 Hz, 2H), 8.14 (d,J=7.7 Hz, 3H), 7.80-7.70 (m, 1H), 7.52 (s, 1H), 7.42-7.35 (m, 1H), 7.27(d, J=12.7 Hz, 1H), 6.88 (dd, J=21.1, 9.4 Hz, 2H), 6.46 (s, 1H), 6.28(d, J=5.9 Hz, 2H), 5.49-5.41 (m, 1H), 3.63 (d, J=2.7 Hz, 2H), 3.18 (d,J=9.7 Hz, 1H), 3.07 (d, J=6.8 Hz, 1H), 2.28 (s, 3H)

Example 474

Synthesis ofN-(1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(474)

Example 474 was prepared (10.7 mg) according to the method presented forthe synthesis of Example 13G utilizing 443H and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid toprovide the title product: MS (m/z): 576.2 [M+H]⁺; ¹H NMR (400 MHz,dmso) δ 9.10 (d, J=8.1 Hz, 1H), 8.75 (s, 1H), 8.66 (s, 1H), 7.46 (dd,J=24.0, 8.4 Hz, 4H), 6.98 (t, J=9.4 Hz, 2H), 6.52 (d, J=6.9 Hz, 2H),5.31 (d, J=7.2 Hz, 1H), 4.74 (s, 2H), 3.00 (dd, J=36.7, 29.6 Hz, 2H),2.46 (m, 4H), 2.33 (m, 1H), 2.27 (m, 1H), 1.63 (s, 4H).

Example 475

Synthesis ofN-(1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetamide(475)

Example 475 was prepared (8.3 mg) according to the method presented forthe synthesis of Example 13 G utilizing 443H and2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid to provide thetitle product: MS (m/z): 532.1 [M+H]⁺; ¹H NMR (400 MHz, dmso) δ 9.42 (d,J=8.0 Hz, 1H), 8.79 (s, 1H), 8.67 (s, 1H), 7.43 (dd, J=21.2, 8.3 Hz,4H), 7.22 (d, J=6.5 Hz, 1H), 7.10 (s, 1H), 6.98 (s, 2H), 6.53 (d, J=7.1Hz, 2H), 5.31 (d, J=7.6 Hz, 1H), 5.11 (s, 2H), 3.17-3.11 (m, 1H),3.13-2.87 (m, 1H), 2.34 (s, 3H), 2.31 (s, 3H).

Example 476

Synthesis ofN-(1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-hydroxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide(476)

A solution ofN-(1-(3-(4-chlorophenyl)pyrazin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide(4.2 mg, 0.008 mmol) and KI (20 mg, 0.12 mmol) in 1 mL acetic acid in asealed tube was subjected to microwave heating at 160° C. for 10 min.After removing the volatile in vacuo, the residue purified by reversephase HPLC eluting with acetonitrile/water to afford 3.3 mg of the titlecompound. MS (m/z): 520.1 [M+H]⁺; ¹H NMR (400 MHz, dmso) δ 11.38 (s,1H), 8.82-8.70 (m, 2H), 8.63 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.44 (d,J=3.5 Hz, 4H), 7.13 (s, 1H), 6.90 (s, 1H), 6.42 (d, J=6.0 Hz, 2H), 6.29(d, J=9.4 Hz, 1H), 5.29 (d, J=7.6 Hz, 1H), 3.45 (d, J=8.8 Hz, 2H),3.21-2.91 (m, 2H).

Example 477

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(1-phenylcyclopropanecarboxamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(477)

The title compound was prepared according to the method presented in thesynthesis of 34E substituting 1-phenylcyclopropanecarboxylic acid for34D and 54B for(S)-2-(3,5-difluorophenyl)-1-(3-(4-methoxyphenyl)pyridin-2-yl)ethanamineto provide the desired compound (18.5 mg, 30%): ¹H NMR (400 MHz, dmso) δ8.45 (dd, 1H), 7.69 (d, 2H), 7.60 (dd, 1H), 7.54-7.48 (m, 1H), 7.42 (d,1H), 7.34 (ddd, 5H), 7.23 (dd, 2H), 6.92 (t, 1H), 6.79 (d, 1H), 6.40 (d,2H), 5.20 (dd, 1H), 2.80 (ddd, 2H), 1.17 (d, 2H), 0.91 (t, 2H); MS (m/z)516.3 [M+H]⁺.

Examples 478 and 479

Synthesis of ethyl3-methyl-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoate (478C)

A 2 dram vial was charged with 3-(trifluoromethyl)-1H-pyrazole (500 mg,3.8 mmol), DMF (5 ml), and KHMDS (1.1 g, 5.5 mmol). The resultingmixture was stirred for 10 minutes and then add ethyl2-bromo-3-methylbutanoate (0.8 ml, 5.3 mmol). Stir at RT until done byLC/MS or TLC. Dilute the reaction with H₂O and extract 2× EtOAc. Thecombined organic layers were washed with brine then dried over sodiumsulfate, concentrated, and purified by flash chromatography to give thedesired compound (450 mg, 46%): MS (m/z) 265.2 [M+H]⁺.

Synthesis of 3-methyl-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoicacid (478D)

A 40 ml vial was charged with ethyl3-methyl-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoate (450 mg, 1.7mmol), MeOH (2 ml), THF (5 ml), H₂O (2 ml), and LiOH (500 mg, 21 mmol).Stir at RT until done by LC/MS. Dilute the reaction with H₂O and extractwith EtOAc. The water layer was acidified with 1 N HCl and extracted 2×EtOAc. The combined organic layers were dried over sodium sulfate,concentrated, and used crude in the next reaction: MS (m/z) 237.0[M+H]⁺.

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(3-methyl-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)butanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(478E and 479)

The title compounds were prepared according to the method presented inthe synthesis of 54G substituting3-methyl-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoic acid for2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid to provide the desiredcompounds (478E, the first peak off HPLC 2.2 mg, 3%; 479, the secondpeak off HPLC, 2.6 mg, 3%): 478E ¹H NMR (400 MHz, dmso) δ 8.63 (d, 1H),8.43 (d, 1H), 7.88 (s, 1H), 7.66 (s, 2H), 7.57 (d, 1H), 7.45 (d, 1H),7.37 (dd, 1H), 7.31 (d, 2H), 6.90 (s, 1H), 6.56 (s, 1H), 6.50 (d, 2H),5.11 (d, 1H), 2.90 (d, 2H), 2.72-2.60 (m, 2H), 1.44 (d, 6H). MS (m/z)590.6 [M+H]⁺. 479 ¹H NMR (400 MHz, dmso) δ 9.21 (d, 1H), 8.60 (d, 1H),7.85 (s, 1H), 7.70 (d, 2H), 7.60 (d, 1H), 7.53 (d, 1H), 7.45-7.28 (m,3H), 6.94 (s, 1H), 6.64 (s, 3H), 5.16 (s, 1H), 4.69 (d, 1H), 2.99 (d,3H), 0.50 (t, 6H); MS (m/z) 591.1 [M+H]⁺.

Example 480

Synthesis of(S)-3-(2-(1-(2-(1H-indol-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(480)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and 2-(1H-indol-3-yl)acetic acid toprovide 5.1 mg the desired compound in a 12% yield: ¹H NMR (400 MHz,dmso) δ 10.75 (s, 1H), 8.71-8.56 (m, 2H), 7.95 (s, 1H), 7.86 (d, 1H),7.74 (s, 1H), 7.62 (dd, 1H), 7.50-7.35 (m, 4H), 7.26 (dd, 2H), 7.04-6.95(m, 2H), 6.91 (t, 1H), 6.83 (t, 1H), 6.50 (d, 2H), 5.18 (dd, 1H), 3.45(q, 2H), 2.95 (d, 2H); MS (m/z) 511.3 [M+H]⁺.

Example 481

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(4-methyl-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(481)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and 2-(4-methyl-1H-indol-3-yl)acetic acidto provide 17.6 mg of the desired compound in a 38% yield: ¹H NMR (400MHz, dmso) δ 10.73 (s, 1H), 8.60 (dd, 1H), 8.28 (d, 1H), 7.95 (s, 1H),7.88 (d, 1H), 7.74 (s, 1H), 7.61 (dd, 1H), 7.42 (ddd, 4H), 7.08 (d, 1H),6.89 (ddd, 3H), 6.56 (d, 1H), 6.46 (d, 2H), 5.21 (dd, 2H), 3.68-3.53 (m,2H), 2.93 (d, 2H), 2.28 (s, 3H); MS (m/z) 525.3 [M+H]⁺.

Examples 482 and 420

Synthesis of N-cyclopropyl-3-isopropyl-1H-pyrazole-5-carboxamide (482B)

A RB was charged with 3-isopropyl-1H-pyrazole-5-carboxylic acid (500 mg,3.2 mmol), DMF (10 ml), HATU (1.2 g, 3.2 mmol), cyclopropanamine (0.45ml, 6.4 mmol), and DiPEA (2.2 ml, 13 mmol). Stir at RT until done byLC/MS or TLC. Dilute the reaction with H₂O and extract 2× EtOAc. Thecombined organic layers were concentrated, and used as is in the nextreaction. MS (m/z) 193.0 [M+H]⁺.

Synthesis of(S)-1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-N-cyclopropyl-5-isopropyl-1H-pyrazole-3-carboxamide(482C) and(S)-1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-N-cyclopropyl-3-isopropyl-1H-pyrazole-5-carboxamide(520)

The title compounds were prepared according to the method presented inthe synthesis of 56B substitutingN-cyclopropyl-3-isopropyl-1H-pyrazole-5-carboxamide for1H-benzo[g]indole to provide the desired compounds (482C (as a 1:1 mixof 482C and 520), 3 mg, 7%; 520, 8 mg, 20%): 482C MS (m/z) 605.5 [M+H]J.520 ¹H NMR (400 MHz, dmso) δ 8.65 (d, 1H), 8.57 (d, 1H), 8.29 (d, 1H),7.63 (s, 1H), 7.58 (d, 2H), 7.43-7.34 (m, 3H), 7.31-7.22 (m, 1H), 6.86(s, 1H), 6.58 (s, 1H), 6.44 (d, 2H), 5.13 (d, 1H), 5.06 (s, 2H), 2.95(d, 2H), 2.82-2.71 (m, 1H), 2.67 (s, 1H), 1.11 (d, 5H), 0.60 (d, 2H),0.46 (s, 2H); MS (m/z) 605.4 [M+H]⁺.

Examples 483 and 484

Synthesis of 2-bromobutanoic acid (483B)

A 40 ml vial was charged with ethyl 2-bromobutanoate (0.7 ml, 5.1 mmol),MeOH (2 ml), THF (5 ml), H₂O (2 ml), and LiOH (1 g, 42 mmol). Stir at RTfor 1 hour. Dilute the reaction with H₂O and extract with EtOAc. Thewater layer was acidified with 1 N HCl and extracted 2× EtOAc. Thecombined organic layers were dried over sodium sulfate, concentrated,and used crude in the next reaction.

Synthesis of5-(2-((1S)-1-(2-bromobutanamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(483C)

The title compound was prepared according to the method presented inExample 54 substituting 2-bromobutanoic acid for2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid to provide the desiredcompound: MS (m/z) 522.0 [M+H]⁺.

Synthesis of 5-(2-((1S)-1-(2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)butanamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(483D and 484)

The title compounds were prepared according to the method presented inthe synthesis of 56B substituting 3,5-bis(difluoromethyl)-1H-pyrazolefor 1H-benzo[g]indole and5-(2-((1S)-1-(2-bromobutanamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamidefor 56A to provide the desired compounds (483D, the first peak off HPLC,3.7 mg, 6%; 484, the second peak off HPLC, 21 mg, 36%): 483D ¹H NMR (400MHz, dmso) δ 8.81 (d, 1H), 8.62 (d, 1H), 7.65 (d, 1H), 7.59 (d, 1H),7.48 (d, 1H), 7.38 (dd, 2H), 7.35-7.26 (m, 1H), 7.15 (s, 1H), 7.10 (s,1H), 7.02 (s, 1H), 6.95 (d, 1H), 6.83 (s, 11H), 6.54 (d, 2H), 5.10 (d,1H), 5.03-4.94 (m, 1H), 2.96 (d, 2H), 1.96 (s, 2H), 0.64 (t, 3H); MS(m/z) 608.8 [M+H]⁺. 484 ¹H NMR (400 MHz, dmso) δ 8.83 (d, 1H), 8.65 (d,1H), 7.66 (s, 2H), 7.61 (d, 1H), 7.47-7.38 (m, 3H), 7.31 (dd, 1H), 7.12(d, 11H), 6.98 (d, 1H), 6.90-6.80 (m, 2H), 6.49 (d, 2?H), 5.08 (d, 1H),5.03-4.93 (m, 1H), 2.96 (t, 2H), 2.10-1.90 (m, 2H), 0.68 (t, 3H); MS(m/z) 608.8 [M+H]⁺.

Example 485

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5,6-dimethyl-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(485)

The title compound was prepared according to the method presented inExample 56 substituting 5,6-dimethyl-1H-indazole for 1H-benzo[g]indoleto provide the desired compound (13.6 mg, 38%): ¹H NMR (400 MHz, dmso) δ8.82 (d, 1H), 8.71-8.65 (m, 1H), 7.80 (s, 1H), 7.66-7.55 (m, 3H), 7.41(dd, 4H), 7.30-7.20 (m, 1H), 7.10 (s, 1H), 6.91 (t, 1H), 6.52 (d, 2H),5.14 (dd, 1H), 4.95 (s, 2H), 2.99 (d, 2H), 2.25 (d, 6H); MS (m/z) 558.4[M+H]⁺.

Example 486

Synthesis of(S)-2-(3-acetyl-2-methyl-1H-indol-1-yl)-N-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide(486)

The title compound was prepared according to the method presented in thesynthesis of 36F utilizing 36E and2-(3-acetyl-2-methyl-1H-indol-1-yl)acetic acid to provide 19.5 mg of thedesired compound in a 29% yield: ¹H NMR (400 MHz, dmso) δ 9.12 (d, 1H),8.69 (dd, 1H), 7.91 (d, 1H), 7.58-7.54 (m, 1H), 7.40 (dd, 3H), 7.24 (t,3H), 7.15-7.05 (m, 2H), 6.98 (t, 1H), 6.50 (d, 2H), 5.15 (dd, 1H), 4.89(d, 2H), 3.04-2.90 (m, 2H), 2.49 (s, 3H), 2.47 (s, 3H); MS (m/z) 558.5[M+H]⁺.

Examples 487 and 488

Synthesis of ethyl 2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)hexanoate

The title compound was prepared according to the method presented inExample 478 substituting ethyl 2-bromohexanoate for ethyl2-bromo-3-methylbutanoate to provide the desired compound: MS (m/z)279.2 [M+H]⁺.

Synthesis of 2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)hexanoic acid (487B)

The title compound was prepared according to the method presented inExample 478 substituting ethyl2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)hexanoate for ethyl2-bromo-3-methylbutanoate to provide the desired compound: MS (m/z)251.0 [M+H]⁺.

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)hexanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(487C and 488)

The title compounds were prepared according to the method presented inthe synthesis of 54G substituting2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)hexanoic acid for2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid to provide the desiredcompounds (487C, the first peak off HPLC, 6.5 mg, 8%; 488, the secondpeak off HPLC, 6.1 mg, 8%): 487C ¹H NMR (400 MHz, dmso) δ 9.11 (d, 1H),8.65-8.59 (m, 1H), 7.84 (s, 1H), 7.69 (d, 2H), 7.62 (dd, 1H), 7.56 (d,1H), 7.44 (s, 1H), 7.39 (dd, 1H), 7.35-7.27 (m, 1H), 6.97 (t, 1H), 6.68(d, 2H), 6.63 (d, 1H), 5.12 (d, 1H), 5.00 (t, 1H), 3.00 (d, 2H),1.78-1.67 (m, 2H), 1.15 (dd, 2H), 0.84 (s, 2H), 0.73 (t, 3H); MS (m/z)605.0 [M+H]⁺. 488 ¹H NMR (400 MHz, dmso) δ 9.02 (d, 1H), 8.65 (d, 1H),7.87 (s, 1H), 7.67-7.57 (m, 3H), 7.47-7.36 (m, 3H), 7.35-7.27 (m, 1H),6.83 (s, 1H), 6.63 (s, 1H), 6.45 (d, 2H), 5.14-4.97 (m, 2H), 2.98 (d,2H), 1.85 (d, 2H), 1.17 (s, 2H), 0.98 (d, 2H), 0.73 (t, 3H); MS (m/z)604.9 [M+H]⁺.

Example 489

Synthesis of (S)-tert-butyl2-(3,5-difluorophenyl)-1-(3-(2-oxoindolin-4-yl)pyridin-2-yl)ethylcarbamate(489B)

A microwave vial was charged with 4-bromoindolin-2-one (100 mg, 0.5mmol), DME:DMF 4:1 (1.5 ml),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (179 mg, 0.8mmol), Pd(PPh₃)₂Cl₂ (16 mg, 0.02 mmol), and KOAc (92 mg, 1 mmol). Heatthe mixture in a microwave at 150° C. for 15 minutes. Then add 50A (200mg, 0.5 mmol), 2 M aq. K₂CO₃ (0.5 ml) and Pd(PPh₃)₂Cl₂ (16 mg, 0.02mmol). Heat the mixture in a microwave at 150° C. for 20 minutes. Allowthe reaction to cool then dilute with H₂O and extract 2× EtOAc. Thecombined organic layers were washed with brine then dried over sodiumsulfate, concentrated, passed through a silica gel plug and concentratedto give the desired compound, which was used as is in the next reaction:MS (m/z) 466.3 [M+H]⁺.

Synthesis of(S)-4-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)indolin-2-one(489C)

The title compound was prepared according to the method presented in thesynthesis of 50C substituting (S)-tert-butyl2-(3,5-difluorophenyl)-1-(3-(2-oxoindolin-4-yl)pyridin-2-yl)ethylcarbamatefor 50B to provide the desired compound: MS (m/z) 366.4 [M+H]⁺.

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(3-(2-oxoindolin-4-yl)pyridin-2-yl)ethyl)acetamide(489D)

The title compound was prepared according to the method presented in thesynthesis of 61F substituting 287C for 61C and 489C for 61E to providethe desired compound (17 mg): ¹H NMR (400 MHz, cd₃od) δ 8.70 (d, 1H),7.66 (s, 1H), 7.57 (s, 1H), 7.40 (s, 1H), 7.26 (s, 1H), 7.18 (s, 1H),6.97 (s, 1H), 6.90 (d, 1H), 6.78 (s, 1H), 6.71 (s, 2H), 6.37 (s, 1H),6.29 (s, 1H), 6.23 (s, 1H), 5.05 (d, 3H), 3.17-3.04 (m, 2H), 2.98 (dd,1H), 2.51 (s, 4H); MS (m/z) 650.2 [M+H]⁺.

Example 490

Synthesis of (S)-tert-butyl2-(3,5-difluorophenyl)-1-(3-(2-oxo-1,2-dihydroquinolin-7-yl)pyridin-2-yl)ethylcarbamate(490B)

The title compound was prepared according to the method presented in thesynthesis of 489B substituting 7-bromoquinolin-2(1H)-one for 489A toprovide the desired compound: MS (m/z) 478.1 [M+H]⁺.

Synthesis of(S)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)quinolin-2(1H)-one(490C)

The title compound was prepared according to the method presented in thesynthesis of 50C substituting (S)-tert-butyl2-(3,5-difluorophenyl)-1-(3-(2-oxo-1,2-dihydroquinolin-7-yl)pyridin-2-yl)ethylcarbamatefor 50B to provide the desired compound: MS (m/z) 378.1 [M+H]⁺.

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(3-(2-oxo-1,2-dihydroquinolin-7-yl)pyridin-2-yl)ethyl)acetamide(490D)

The title compound was prepared according to the method presented in thesynthesis of 61F substituting 287C for 61C and 490C for 61E to providethe desired compound (17 mg): ¹H NMR (400 MHz, cd₃od) δ 8.74-8.66 (m,1H), 7.97 (d, 1H), 7.67-7.56 (m, 2H), 7.41 (dd, 1H), 7.06 (s, 1H), 6.94(s, 1H), 6.81 (s, 1H), 6.65 (dd, 2H), 6.20 (d, 2H), 5.49 (t, 1H), 5.10(s, 2H), 3.00 (d, 2H), 2.62-2.42 (m, 4H); MS (m/z) 662.3 [M+H]⁺.

Examples 491 and 557

Synthesis of tert-butyl (1H-indol-5-yl)methylcarbamate (491B)

A round bottom flask was charged with (1H-indol-5-yl)methanamine (2 g,14 mmol), (BOC)₂O (3 g, 14 mmol), DCM (100 ml), and DiPEA (2.4 ml, 14mmol). The reaction was stirred until done by LC/MS. The reaction wasdiluted with H₂O and extracted 2×DCM and IX EtOAc. The combined organiclayer was dried over sodium sulfate, filtered, concentrated and usedcrude in the next reaction. MS (m/z) 246.9 [M+H]⁺

Synthesis of methyl2-(5-((tert-butoxycarbonylamino)methyl)-1H-indol-3-yl)-2-oxoacetate(491C)

A round bottom flask was charged with ether (20 mil) and tert-butyl(1H-indol-5-yl)methylcarbamate (3 g, 12 mmol) followed by slow additionof oxalyl chloride (1 ml, 11 mmol). The reaction was stirred until colorchanges and was then filtered. The solid was dissolved in MeOH (5 ml)and then precipitated out by adding ether. The mixture was filtered anddried under vacuum to obtain 1.4 g of the desired compound as the HClsalt which was used with no further purification. The yield was 36%.

Synthesis of methyl2-(5-((tert-butoxycarbonylamino)methyl)-1H-indol-3-yl)acetate (491D)

A round bottom is charged with methyl2-(5-((tert-butoxycarbonylamino)methyl)-1H-indol-3-yl)-2-oxoacetate (1.4g, 4 mmol), dioxane (100 ml), Pd/C (0.5 g), H₂NaO2P•H2O (1 g, 9 mmol),and H₂O (40 ml). The resulting mixture was stirred at 120° C. until doneas indicated by LC/MS. The reaction mixture was cooled to RT andfiltered over a plug of celite, rinsing with ethyl acetate. The layerswere partitioned and the organic layer was dried over sodium sulfate,filtered, concentrated and purified by flash chromatography to give thedesired compound as an oil (660 mg, 52%): MS (m/z) 318.8 [M+H]⁺

Synthesis of2-(5-((tert-butoxycarbonylamino)methyl)-1H-indol-3-yl)acetic acid (491E)

The title compound was prepared according to the method presented inExample 478 substituting ethyl2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)hexanoate for methyl2-(5-((tert-butoxycarbonylamino)methyl)-1H-indol-3-yl)acetate to providethe desired compound: MS (m/z) 305.1 [M+H]⁺.

Synthesis of (S)-tert-butyl(3-(2-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-1H-indol-5-yl)methylcarbamate(557)

The title compound was prepared according to the method presented in thesynthesis of 36F utilizing 36E and2-(5-((tert-butoxycarbonylamino)methyl)-1H-indol-3-yl)acetic acid toprovide 20 mg of the desired compound in a 29% yield: ¹H NMR (400 MHz,dmso) δ 10.72 (s, 1H), 8.63 (d, 1H), 8.50 (d, 1H), 7.51 (d, 1H), 7.36(dd, 3H), 7.28-7.11 (m, 5H), 7.01 (s, 1H), 6.97-6.87 (m, 2H), 6.37 (d,2H), 5.15 (d, 1H), 4.09 (s, 2H), 3.46 (s, 2H), 2.93 (s, 2H), 1.34 (s,9H); MS (m/z) 631.5 [M+H]⁺.

Synthesis of(S)-2-(5-(aminomethyl)-1H-indol-3-yl)-N-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide(491F)

A round bottom flask was charged (S)-tert-butyl(3-(2-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-1H-indol-5-yl)methylcarbamate(18 mg, 0.3 mmol) and TFA:DCM 1:1 (1 ml). The reaction was stirred atroom temperature until done by LC/MS then concentrated 2× from DCM andthen dissolved in ACN/H₂O and dried by lyopholization to obtain thedesired compound (15 mg, 99%): ¹H NMR (400 MHz, dmso) δ 10.94 (s, 1H),8.64 (dd, 1H), 8.54 (d, 1H), 8.00 (s, 2H), 7.54 (dd, 1H), 7.47 (s, 1H),7.42-7.30 (m, 4H), 7.19 (d, 2H), 7.11 (d, 2H), 6.91 (t, 1H), 6.40 (d,2H), 5.14 (dd, 1H), 3.99 (d, 2H), 3.48 (dd, 2H), 2.99-2.87 (m, 2H); MS(m/z) 531.4 [M+H]⁺.

Example 492

Synthesis of2-(4-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)aceticacid (492A)

The title compound was prepared according to the method presented inExample 491 substituting ethyl2-(4-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetatefor 491D to provide the desired compound: MS (m/z) 249.0 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide (492B)

The title compound was prepared according to the method presented in thesynthesis of 54G utilizing 54B and2-(4-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetic acid to provide 15.3 mg of the desired compound in a 19%yield: ¹H NMR (400 MHz, cd₃od) δ 8.70 (d, 1H), 7.63-7.57 (m, 1H), 7.48(s, 1H), 7.41 (dd, 1H), 7.30 (s, 1H), 7.25-7.16 (m, 1H), 6.67 (d, 1H),6.33 (d, 2H), 5.36 (t, 1H), 4.95 (s, 2H), 3.33 (s, 2H), 3.08 (dd, 4H),2.96 (d, 2H); MS (m/z) 602.5 [M+H]⁺.

Example 493

Synthesis of(S)-5-(2-(1-(2-(3,5-bis(difluoromethyl)-4-methyl-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(493)

A 40 ml vial was charged with 555C (100 mg, 0.15 mmol), DMF (1 ml), DME(4 ml), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.1 ml), Pd(OAc)₂(10 mg, 0.01 mmol), XPhos (14 mg, 0.02 mmol) and 2N K₃PO₄ (0.6 ml). Heatthe stirring mixture overnight at 86° C. Allow the reaction to cool thendilute with H₂O and extract 2× EtOAc. The combined organic layers werewashed with brine then dried over sodium sulfate, concentrated, andpurified by HPLC to give 8 mg of the desired compound. The yield was 9%:¹H NMR (400 MHz, cd₃od) δ 8.73-8.67 (m, 1H), 7.65-7.56 (m, 1H),7.49-7.37 (m, 2H), 7.29 (s, 1H), 7.26-7.16 (m, 1H), 7.09-6.68 (m, 2H),6.65 (t, 1H), 6.30 (d, 2H), 5.36-5.28 (m, 1H), 4.97 (s, 2H), 3.12-2.96(m, 2H), 2.21 (s, 3H); MS (m/z) 594.3 [M+H]⁺.

Example 494

Synthesis of(S)-5-(2-(1-(2-(6-chloro-1H-indol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(494)

The title compound was prepared according to the method presented inExample 56 substituting 6-chloro-1H-indole for 1H-benzo[g]indole toprovide the desired compound (3 mg, 8%): ¹H NMR (400 MHz, dmso) δ 8.98(d, 1H), 8.71 (s, 1H), 7.64 (s, 2H), 7.58 (d, 1H), 7.46 (d, 2H), 7.40(d, 2H), 7.27 (d, 1H), 7.22 (s, 1H), 7.18 (d, 1H), 6.95 (d, 1H), 6.90(s, 1H), 6.55 (d, 2H), 6.36 (d, 1H), 5.13 (d, 1H), 4.78 (s, 2H), 3.00(d, 2H); MS (m/z) 563.8 [M+H]⁺.

Example 495

Synthesis of(S)-3-(2-(1-(2-(3-acetyl-2-methyl-1H-indol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(495)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and2-(3-acetyl-2-methyl-1H-indol-1-yl)acetic acid to provide 20 mg of thedesired compound in a 32% yield: ¹H NMR (400 MHz, dmso) δ 9.10 (d, 1H),8.75-8.65 (m, 1H), 7.90 (dd, 3H), 7.75 (s, 1H), 7.65 (dd, 1H), 7.49-7.35(m, 4H), 7.22 (d, 1H), 7.15-7.02 (m, 2H), 6.94 (t, 1H), 6.58 (d, 2H),5.17 (d, 1H), 4.86 (d, 2H), 3.01 (d, 2H), 2.48 (s, 3H), 2.46 (s, 2H); MS(m/z) 567.4 [M+H]⁺.

Example 496

Synthesis of 2-(5-(tert-butoxycarbonylamino)-1H-indol-3-yl)acetic acid(496A)

The title compound was prepared according to the method presented inExample 54 substituting 35C for 54E to provide the desired compound: MS(m/z) 291.1 [M+H]⁺.

Synthesis of (S)-tert-butyl3-(2-(1-(3-(3-carbamoylphenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-1H-indol-5-ylcarbamate(496B)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and2-(5-(tert-butoxycarbonylamino)-1H-indol-3-yl)acetic acid to provide 11mg of the desired compound in a 16% yield: ¹H NMR (400 MHz, dmso) δ10.65 (s, 1H), 8.93 (s, 1H), 8.62 (d, 1H), 8.51 (d, 1H), 7.96 (s, 1H),7.85 (d, 1H), 7.68 (s, 1H), 7.58 (d, 2H), 7.43 (t, 1H), 7.37 (t, 3H),7.14 (d, 1H), 6.97 (s, 2H), 6.84 (t, 1H), 6.37 (d, 2H), 5.22 (d, 1H),3.43 (s, 2H), 2.94 (d, 2H), 1.42 (s, 9H); MS (m/z) 626.2 [M+H]⁺.

Example 497

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(2-methyl-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(497)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and 2-(2-methyl-1H-indol-3-yl)acetic acidto provide 22 mg of the desired compound in a 37% yield: ¹H NMR (400MHz, dmso) δ 10.63 (s, 1H), 8.64 (dd, 1H), 8.51 (d, 1H), 7.94 (s, 1H),7.86 (d, 1H), 7.76 (s, 1H), 7.61 (dd, 1H), 7.44 (d, 2H), 7.39 (dd, 2H),7.19 (d, 1H), 7.12 (d, 1H), 6.98-6.84 (m, 2H), 6.76 (t, 1H), 6.50 (d,2H), 5.14 (dd, 1H), 3.39 (q, 2H), 2.93 (d, 2H), 2.18 (s, 3H); MS (m/z)525.4 [M+H]⁺.

Example 498

Synthesis of 1-(4,5-dimethyl-2-nitrostyryl)pyrrolidine (498B)

The title compound was prepared according to the method presented inExample 536 substituting 1,2,4-trimethyl-5-nitrobenzene for 536C toprovide the desired compound.

Synthesis of 5,6-dimethyl-1H-indole (498C)

The title compound was prepared according to the method presented inExample 536 substituting 1-(4,5-dimethyl-2-nitrostyryl)pyrrolidine for536D to provide the desired compound: MS (m/z) 146.4 [M+H]⁺.

Synthesis of methyl 2-(5,6-dimethyl-1H-indol-1-yl)acetate (498D)

The title compound was prepared according to the method presented inExample 478 substituting methyl 2-bromoacetate for 478B and5,6-dimethyl-1H-indole for 478A to provide the desired compound: MS(m/z) 218.2 [M+H]⁺.

Synthesis of 2-(5,6-dimethyl-1H-indol-1-yl)acetic acid (498E)

The title compound was prepared according to the method presented inExample 478 substituting methyl 2-(5,6-dimethyl-1H-indol-1-yl)acetatefor 478C to provide the desired compound: MS (m/z) 204.2 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5,6-dimethyl-1H-indol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(498F)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting 2-(5,6-dimethyl-1H-indol-1-yl)acetic acidfor 54F to provide the desired compound (5 mg, 9%): ¹H NMR (400 MHz,dmso) δ 8.83 (d, 1H), 8.67 (d, 1H), 7.69-7.56 (m, 3H), 7.47 (d, 1H),7.40 (dd, 2H), 7.30-7.22 (m, 1H), 7.20 (s, 1H), 7.00 (d, 1H), 6.92 (t,1H), 6.84 (s, 1H), 6.58 (d, 2H), 6.17 (d, 1H), 5.12 (d, 1H), 4.68 (s,2H), 3.00 (d, 2H), 2.19 (d, 6H); MS (m/z) 557.6 [M+H]⁺.

Example 499 Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(2,4-dimethoxyphenyl)acetamido)ethyl)pyridin-3-yl)benzamide(499)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and 2-(2,4-dimethoxyphenyl)acetic acid toprovide 21 mg of the desired compound in a 40% yield: ¹H NMR (400 MHz,dmso) δ 8.65 (d, 1H), 8.30 (d, 1H), 7.94 (s, 1H), 7.88 (d, 1H), 7.74 (s,1H), 7.66-7.59 (m, 1H), 7.48 (t, 1H), 7.45-7.35 (m, 3H), 6.91 (t, 1H),6.81 (d, 1H), 6.46 (d, 2H), 6.42 (d, 1H), 6.33 (dd, 1H), 5.23-5.13 (m,1H), 3.68 (s, 3H), 3.59 (s, 3H), 3.24 (s, 2H), 2.92 (d, 2H); MS (m/z)532.2[M+H]⁺.

Example 500

Synthesis of(S)-3-(2-(1-(2-(3-acetyl-1H-indol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(500)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and 2-(3-acetyl-1H-indol-1-yl)acetic acidto provide 22.6 mg of the desired compound in a 37% yield: ¹H NMR (400MHz, dmso) δ 9.11 (d, 1H), 8.72 (dd, 1H), 8.09 (d, 2H), 7.94 (s, 1H),7.87 (d, 1H), 7.74 (s, 1H), 7.65 (dd, 1H), 7.49-7.34 (m, 4H), 7.11 (td,2H), 7.03 (s, 1H), 6.96 (t, 1H), 6.60 (d, 2H), 5.18 (dd, 1H), 4.86 (s,2H), 3.09-2.96 (m, 2H), 2.35 (s, 3H); MS (m/z) 553.34 [M+H]⁺.

Example 501 Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-phenylacetamido)ethyl)pyridin-3-yl)benzamide(501)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and 2-phenylacetic acid to provide 21 mgof the desired compound in a 40% yield: ¹H NMR (400 MHz, dmso) δ 8.72(d, 1H), 8.66 (d, 1H), 7.95 (s, 1H), 7.88 (d, 1H), 7.76 (s, 1H), 7.62(d, 1H), 7.43 (ddd, 4H), 7.18-7.10 (m, 3H), 7.04 (d, 2H), 6.89 (t, 1H),6.51 (d, 2H), 5.15 (d, 1H), 3.42 (d, 1H), 3.28 (d, 1H), 2.96 (d, 2H); MS(m/z) 472.3 [M+H]⁺.

Example 502

Synthesis of ethyl tert-butyl (1H-indol-6-yl)methylcarbamate (502B)

The title compound was prepared according to the method presented inExample 491 substituting (1H-indol-6-yl)methanamine for ethyl 491A toprovide the desired compound: MS (m/z) 246.7 [M+H]⁺.

Synthesis of methyl2-(6-((tert-butoxycarbonylamino)methyl)-1H-indol-3-yl)-2-oxoacetate(502C)

The title compound was prepared according to the method presented inExample 491 substituting tert-butyl (1H-indol-6-yl)methylcarbamate for491B to provide the desired compound: MS (m/z) 333.9 [M+H]⁺.

Synthesis of methyl2-(6-((tert-butoxycarbonylamino)methyl)-1H-indol-3-yl)acetate (502D)

The title compound was prepared according to the method presented inExample 491 substituting methyl2-(6-((tert-butoxycarbonylamino)methyl)-1H-indol-3-yl)-2-oxoacetate for491C to provide the desired compound: MS (m/z) 319.0 [M+H]⁺.

Synthesis of2-(6-((tert-butoxycarbonylamino)methyl)-1H-indol-3-yl)acetic acid (502E)

The title compound was prepared according to the method presented inExample 491 substituting ethyl methyl2-(6-((tert-butoxycarbonylamino)methyl)-1H-indol-3-yl)acetate for 491Dto provide the desired compound: MS (m/z) 304.9 [M+H]⁺.

Synthesis of (S)-tert-butyl(3-(2-(1-(3-(3-carbamoylphenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-1H-indol-6-yl)methylcarbamate(502F)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and2-(6-((tert-butoxycarbonylamino)methyl)-1H-indol-3-yl)acetic acid toprovide 30 mg of the desired compound in a 44% yield: ¹H NMR (400 MHz,dmso) δ 10.69 (s, 1H), 8.66-8.62 (m, 1H), 8.54 (d, 1H), 7.93 (s, 1H),7.86 (d, 1H), 7.73 (s, 1H), 7.63-7.56 (m, 1H), 7.48-7.35 (m, 4H), 7.27(s, 1H), 7.21 (d, 1H), 7.12 (s, 1H), 6.96 (s, 1H), 6.88 (t, 1H), 6.75(d, 1H), 6.47 (d, 2H), 5.19 (d, 1H), 4.12 (d, 2H), 3.44 (d, 2H), 2.94(d, 2H), 1.36 (s, 9H); MS (m/z) 640.2 [M+H]⁺.

Example 503

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(dimethylamino)-2-(4-fluorophenyl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(503)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting 2-(dimethylamino)-2-(4-fluorophenyl)aceticacid for 54F to provide the desired compound (the first peak off HPLC, 3mg, 4%): ¹H NMR (400 MHz, dmso) δ 10.07-9.97 (m, 1H), 9.51-9.44 (m, 1H),8.45 (s, 1H), 7.72 (s, 2H), 7.58 (d, 1H), 7.49 (d, 1H), 7.38-7.21 (m,6H), 6.98 (s, 1H), 6.68 (d, 2H), 5.26 (s, 1H), 4.80 (s, 1H), 3.07 (s,2H), 2.49 (s, 3H), 2.30 (s, 3H); MS (m/z) 551.3 [M+H]⁺.

Example 504

Synthesis of ethyl2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)butanoate(504C)

A RB was charged with 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole(1 g, 5 mmol), KHMDS (1.3 g, 7 mmol), and THF (5 ml). The resultingmixture was stirred for 10 minutes then ethyl 2-bromobutanoate (0.7 mg,5 mmol) was added. The mixture was stirred until done by LC/MS thendiluted with H₂O and extracted 2× EtOAc. The organic layers were driedover sodium sulfate, and concentrated to afford the desired compoundwhich was used crude in the next reaction; MS (m/z) 305.3 [M+H]⁺.

Synthesis of2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)butanoic acid(504D)

The title compound was prepared according to the method presented inExample 54 substituting ethyl2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)butanoate for54E to provide the desired compound: MS (m/z) 277.3 [M+H]⁺.

Synthesis of5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)butanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(504E)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)butanoic acidfor 54F to provide the desired compound (24 mg, 28%): MS (m/z) 631.3[M+H]⁺.

Example 505 Synthesis of(S)-5-(2-(1-(2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(505)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting 3,5-bis(difluoromethyl)-1H-pyrazole for1H-benzo[g]indole to provide the desired compound (25 mg, 62%): ¹H NMR(400 MHz, dmso) δ 9.01 (d, 1H), 8.68 (dd, 1H), 7.68-7.57 (m, 3H), 7.41(dd, 2H), 7.38 (d, 1H), 7.33-7.24 (m, 1H), 7.11 (d, 1H), 6.97 (d, 1H),6.89 (d, 1H), 6.80 (d, 1H), 6.51 (d, 2H), 5.21-5.10 (m, 1H), 4.94 (s,2H), 2.98 (dd, 2H); MS (m/z) 579.3 [M+H]⁺.

Example 506

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(3,4,5-trimethyl-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(506)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and2-(3,4,5-trimethyl-1H-pyrazol-1-yl)acetic acid to provide 21 mg of thedesired compound in a 40% yield: ¹H NMR (400 MHz, dmso) δ 8.67 (dd, 2H),7.94 (s, 1H), 7.89 (d, 1H), 7.72 (s, 1H), 7.65 (dd, 1H), 7.48 (t, 1H),7.45-7.38 (m, 3H), 6.91 (t, 1H), 6.48 (d, 2H), 5.18 (dd, 1H), 4.60 (s,2H), 3.04-2.88 (m, 2H), 1.99 (s, 3H), 1.87 (s, 3H), 1.78 (s, 3H); MS(m/z) 504.2 [M+H]⁺.

Example 507

Synthesis of5-(2-((1S)-1-(2-chloropropanamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(507A)

The title compound was prepared according to the method presented inExample 56 substituting 2-chloropropanoyl chloride for 2-chloroacetylchloride to provide the desired compound: MS (m/z) 462.9 [M+H]⁺.

Synthesis of5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)propanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(507B)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting 3-(trifluoromethyl)-1H-pyrazole for1H-benzo[g]indole and 507A for 56A to provide the desired compound (27mg, 80%): MS (m/z) 562.3 [M+H]⁺.

Example 508

Synthesis of (S)-tert-butyl2-(3,5-difluorophenyl)-1-(3-(1-oxoisoindolin-5-yl)pyridin-2-yl)ethylcarbamate(508B)

The title compound was prepared according to the method presented in thesynthesis of 489B substituting 5-bromoisoindolin-1-one for 489A toprovide the desired compound: MS (m/z) 466.2 [M+H]⁺.

Synthesis of(S)-5-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)isoindolin-1-one(508C)

The title compound was prepared according to the method presented in thesynthesis of 50C substituting of (S)-tert-butyl2-(3,5-difluorophenyl)-1-(3-(1-oxoisoindolin-5-yl)pyridin-2-yl)ethylcarbamatefor 50B to provide the desired compound: MS (m/z) 366.1 [M+H]⁺.

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(3-(1-oxoisoindolin-5-yl)pyridin-2-yl)ethyl)acetamide(508D)

The title compound was prepared according to the method presented in thesynthesis of 61F substituting 287C for 61C and 508C for 61E to providethe desired compound (34 mg): ¹H NMR (400 MHz, cd₃od) δ 8.78-8.68 (m,1H), 7.76 (d, 1H), 7.63 (dd, 1H), 7.43 (dd, 1H), 7.15 (s, 2H), 6.87 (d,1H), 6.75-6.63 (m, 1H), 6.26 (d, 2H), 5.43-5.32 (m, 1H), 5.08 (s, 2H),4.42 (q, 2H), 3.16-2.93 (m, 3H), 2.66-2.39 (m, 4H); MS (m/z) 650.4[M+H]⁺.

Example 509

Synthesis of(S)-5-(2-(1-(2-(3-acetyl-7-ethyl-1H-indol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(509)

The title compound was prepared according to the method presented in thesynthesis of 54G utilizing 54B and2-(3-acetyl-7-ethyl-1H-indol-1-yl)acetic acid to provide 15 mg of thedesired compound in a 18% yield: ¹H NMR (400 MHz, dmso) δ 9.10 (d, 1H),8.69 (dd, 1H), 8.12 (s, 1H), 8.01 (d, 1H), 7.64 (s, 2H), 7.60 (dd, 1H),7.52-7.48 (m, 1H), 7.41 (dd, 2H), 7.32-7.24 (m, 1H), 7.07-6.92 (m, 2H),6.86 (d, 1H), 6.63 (d, 2H), 5.14 (dd, 1H), 4.98 (s, 2H), 3.02 (d, 2H),2.52 (dd, 3H), 2.33 (s, 3H); MS (m/z) 599.7 [M+H]⁺.

Example 510

Synthesis of(S)-3-(2-(1-(2-(3-chlorophenyl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(510)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and 2-(3-chlorophenyl)acetic acid toprovide 18 mg of the desired compound in a 40% yield: ¹H NMR (400 MHz,dmso) δ 8.79 (d, 1H), 8.67 (dd, 1H), 7.95 (s, 1H), 7.89 (d, 1H), 7.76(s, 1H), 7.63 (dd, 1H), 7.44 (ddd, 4H), 7.19 (d, 2H), 7.11 (s, 1H), 7.01(d, 1H), 6.88 (t, 1H), 6.50 (d, 2H), 5.15 (dd, 1H), 3.37 (dd, 21H), 2.96(d, 2H); MS (m/z) 506.6 [M+H]⁺.

Example 511

Synthesis of ethyl2-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoate

The title compound was prepared according to the method presented inExample 478 substituting 504B for 478B to provide the desired compound:MS (m/z) 291.1 [M+H]⁺.

Synthesis of2-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoic acid(511B)

The title compound was prepared according to the method presented inExample 478 substituting ethyl2-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoate for 478Cto provide the desired compound: MS (m/z) 263.1 [M+H]⁺.

Synthesis of 5-(2-((1S)-1-(2-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)butanamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(511C)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting2-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoic acid for2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid to provide the desiredcompound (32 mg, 39%): MS (m/z) 616.4 [M+H]⁺.

Examples 512 and 528

Synthesis of tert-butyl2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetate

The title compound was prepared according to the method presented inExample 478 substituting tert-butyl 2-bromoacetate for ethyl2-bromo-3-methylbutanoate to provide the desired compound: MS (m/z)285.0 [M+H]⁺.

Synthesis of 2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetic acid(512A)

A round bottom flask was charged with tert-butyl2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetate (1.3 g, 4.6 mmol) andTFA:DCM 1:1 (4 ml). The reaction was stirred at room temperature untildone by LC/MS then concentrated 2× from DCM. The crude mixture was usedas is in next reaction. MS (m/z) 227.0 [M+H]J.

Synthesis of(S)-2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)-N-(1-(3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide(512B)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetic acid for2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid and 55D for 54B toprovide the desired compound: MS (m/z) 521.9 [M+H]⁺.

Synthesis of(S)—N-(1-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetamide(512C) and(S)-2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(pyridin-2-yl)ethyl)acetamide(528)

A microwave vial was charged with 512B (100 mg, 0.2 mmol), DMF (0.5 ml),DME (1.5 ml),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(51 mg, 0.2 mmol), Pd(PPh₃)₄ (11 mg, 0.01 mmol) and K₂CO₃ (39 mg, 0.3mmol) dissolved in water (0.3 ml). Microwave the mixture at 150° C. for30 minutes. Allow the reaction to cool then dilute with H₂O and extract2× EtOAc. The combined organic layers were washed with brine then driedover sodium sulfate, concentrated, and purified by HPLC to give thedesired compounds (512C, 5 mg, 5%) and (528, 5 mg, 6%): 512C ¹H NMR (400MHz, dmso) δ 11.76 (s, 1H), 8.96 (s, 1H), 8.68 (d, 1H), 7.95 (s, 1H),7.64 (d, 2H), 7.50 (s, 1H), 7.46-7.37 (m, 1H), 7.11 (d, 1H), 6.97 (d,2H), 6.80 (d, 1H), 6.41 (d, 3H), 5.19 (d, 1H), 4.96 (s, 2H), 3.05 (d,1H), 2.97 (d, 1H); MS (m/z) 559.1 [M+H]⁺; 528 ¹H NMR (400 MHz, dmso) δ8.89 (d, 1H), 8.55 (d, 1H), 7.76 (t, 1H), 7.37-7.28 (m, 2H), 7.13 (d,1H), 7.07-6.92 (m, 2H), 6.84 (dd, 4H), 5.13 (d, 1H), 4.97 (q, 2H), 3.17(dd, 1H), 3.07-2.95 (m, 1H); MS (m/z) 443.0 [M+H]⁺.

Example 513

Synthesis of(S)—N-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-(trifluoromethyl)-1H-indol-3-yl)acetamide(513)

The title compound was prepared according to the method presented in thesynthesis of 36F utilizing 36E and 54F to provide 17.8 mg of the desiredcompound in a 30% yield: ¹H NMR (400 MHz, dmso) δ 11.25 (s, 1H), 8.67(d, 1H), 8.63 (dd, 1H), 7.82 (s, 1H), 7.53 (dd, 1H), 7.46 (d, 1H), 7.36(dd, 3H), 7.29 (d, 1H), 7.23 (d, 1H), 7.15 (d, 2H), 6.87 (t, 1H), 6.38(d, 2H), 5.14 (q, 1H), 3.55 (s, 2H), 2.91 (t, 2H); MS (m/z) 570.1[M+H]⁺.

Example 514

Synthesis of(S)-5-(2-(1-(2-(1H-pyrrolo[3,2-c]pyridin-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(514)

The title compound was prepared according to the method presented inExample 56 substituting 1H-pyrrolo[3,2-c]pyridine for 1H-benzo[g]indoleto provide the desired compound (23 mg, 62%): ¹H NMR (400 MHz, dmso) δ9.21 (s, 1H), 9.12 (d, 1H), 8.72 (dd, 1H), 8.39 (d, 1H), 7.75 (d, 1H),7.70 (d, 1H), 7.62 (dd, 3H), 7.52-7.46 (m, 1H), 7.43 (dd, 1H), 7.35 (s,1H), 7.32-7.23 (m, 1H), 6.98 (d, 1H), 6.90 (t, 1H), 6.55 (d, 2H), 5.15(dd, 1H), 5.07 (d, 2H), 3.10-2.96 (m, 2H); MS (m/z) 530.5 [M+H]⁺.

Example 515

Synthesis of 5-(2-((1S)-1-(2-cyclopentyl-2-phenylacetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(515)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting 2-cyclopentyl-2-phenylacetic acid for 54Fto provide the desired compound (the second peak off HPLC, 12 mg, 16%):¹H NMR (400 MHz, dmso) δ 10.16-10.05 (m, 1H), 9.58 (s, 1H), 8.68 (d,1H), 7.79-7.65 (m, 3H), 7.63 (s, 1H), 7.50 (s, 1H), 7.48-7.35 (m, 2H),7.35-7.28 (m, 2H), 7.18 (t, 2H), 6.78 (s, 1H), 6.35 (d, 2H), 5.20 (s,1H), 4.78 (s, 1H), 2.91 (d, 3H), 2.58 (s, 4H), 2.33 (s, 4H); MS (m/z)558.6 [M+H]⁺.

Example 516

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(516)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine for1H-benzo[g]indole to provide the desired compound (1 mg, 2%): ¹H NMR(400 MHz, cd₃od) δ 8.71 (s, 1H), 7.57 (d, 1H), 7.55-7.49 (m, 1H), 7.40(d, 1H), 7.21 (d, 2H), 6.72-6.62 (m, 1H), 6.35 (s, 2H), 5.32 (s, 1H),4.29 (s, 2H), 3.48 (d, 2H), 3.17-3.00 (m, 4H), 2.99-2.89 (m, 2H); MS(m/z) 603.3 [M+H]⁺.

Example 517

Synthesis of methyl 2-(5-fluoro-2-methyl-1H-indol-3-yl)-2-oxoacetatehydrochloride (517B)

The title compound was prepared according to the method presented inExample 54 substituting 5-fluoro-2-methyl-1H-indole for 54C to providethe desired compound: MS (m/z) 236.3 [M+H]⁺.

Synthesis methyl 2-(5-fluoro-2-methyl-1H-indol-3-yl)acetate (517C)

The title compound was prepared according to the method presented inExample 54 substituting of methyl2-(5-fluoro-2-methyl-1H-indol-3-yl)-2-oxoacetate hydrochloride for 54Dto provide the desired compound: MS (m/z) 222.1 [M+H]⁺.

Synthesis of 2-(5-fluoro-2-methyl-1H-indol-3-yl)acetic acid (517D)

The title compound was prepared according to the method presented inExample 54 substituting methyl2-(5-fluoro-2-methyl-1H-indol-3-yl)acetate for 54E to provide thedesired compound MS (m/z) 208.2 [M+H]⁺.

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(5-fluoro-2-methyl-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(517E)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and2-(5-fluoro-2-methyl-1H-indol-3-yl)acetic acid to provide 17 mg of thedesired compound in a 27% yield: ¹H NMR (400 MHz, dmso) δ 10.75 (s, 1H),8.64 (dd, 1H), 8.59 (d, 1H), 7.94 (s, 1H), 7.87 (d, 1H), 7.75 (s, 1H),7.60 (dd, 1H), 7.45 (d, 2H), 7.39 (dd, 2H), 7.10 (dd, 1H), 7.04 (dd,1H), 6.86 (t, 1H), 6.76-6.65 (m, 1H), 6.47 (d, 2H), 5.13 (t, 1H),3.43-3.30 (m, 2H), 2.93 (d, 2H), 2.18 (s, 3H); MS (m/z) 543.8 [M+H]⁺.

Example 518 Synthesis of(S)-5-(2-(I-(2-(5,6-dichloro-1H-benzo[d]imidazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(518)

The title compound was prepared according to the method presented inExample 56 substituting 5,6-dichloro-1H-benzo[d]imidazole for1H-benzo[g]indole to provide the desired compound (19 mg, 45%): ¹H NMR(400 MHz, dmso) δ 9.13 (d, 1H), 8.71 (d, 1H), 8.21 (s, 1H), 7.88 (s,1H), 7.61 (dd, 3H), 7.53 (s, 1H), 7.47 (d, 1H), 7.44-7.35 (m, 2H),7.31-7.23 (m, 1H), 6.89 (t, 1H), 6.55 (d, 2H), 5.20-5.10 (m, 1H), 4.92(s, 2H), 3.02 (d, 2H); MS (m/z) 599.3 [M+H]⁺.

Example 519

Synthesis of 5-(2-((1S)-1-(2-(5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propanamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(519)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole for 1H-benzo[g]indole and507A for 56A to provide the desired compound (23 mg, 64%): MS (m/z)602.3 [M+H]⁺.

Example 521

Synthesis of(S)-1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-5-isopropyl-1H-pyrazole-3-carboxylicacid (521)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting 5-isopropyl-1H-pyrazole-3-carboxylic acidfor 1H-benzo[g]indole to provide the desired compound (2 mg, 5%): ¹H NMR(400 MHz, dmso) δ 8.71 (d, 1H), 8.65 (d, 1H), 7.69-7.56 (m, 3H),7.48-7.36 (m, 3H), 7.34-7.26 (m, 1H), 6.89 (t, 1H), 6.50 (d, 3H), 5.16(d, 1H), 4.59 (s, 2H), 3.03-2.88 (m, 4H), 1.18 (d, 6H); MS (m/z) 566.4[M+H]⁺.

Example 522

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(6-methyl-1H-pyrrolo[3,2-c]pyridin-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(522)

The title compound was prepared according to the method presented inExample 56 substituting 6-methyl-1H-pyrrolo[3,2-c]pyridine for1H-benzo[g]indole to provide the desired compound (9 mg, 24%): ¹H NMR(400 MHz, dmso) δ 9.09 (d, 2H), 8.71 (d, 1H), 7.62 (dd, 4H), 7.54 (s,1H), 7.49 (d, 1H), 7.43 (dd, 1H), 7.36 (s, 1H), 7.33-7.25 (m, 1H), 6.91(s, 1H), 6.88 (d, 1H), 6.57 (d, 2H), 5.16 (s, 1H), 4.98 (d, 2H), 3.02(d, 2H), 2.63 (s, 3H); MS (m/z) 544.5 [M+H]⁺.

Example 523

Synthesis of(S)-1-(2-(1-(3-(3-carbamoyl-4-fluorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-N,4-dimethyl-1H-benzo[d]imidazole-2-carboxamide(523)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting2-(4-methyl-2-(methylcarbamoyl)-1H-benzo[d]imidazol-1-yl)acetic acid for54F to provide the desired compound (24 mg, 37%): ¹H NMR (400 MHz, dmso)δ 9.29 (d, 1H), 8.71 (dd, 1H), 8.25 (d, 1H), 7.72 (d, 1H), 7.69-7.60 (m,3H), 7.54-7.48 (m, 1H), 7.48-7.35 (m, 4H), 7.33-7.24 (m, 1H), 6.93 (t,1H), 6.60 (d, 2H), 5.21-5.07 (m, 4H), 4.01 (q, 2H), 3.02 (dd, 2H), 2.58(d, 3H); MS (m/z) 601.4 [M+H]⁺.

Example 524

Synthesis of (S)-tert-butyl1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethylcarbamate(524B)

The title compound was prepared according to the method presented in thesynthesis of 489B starting from step 2 and substituting4-chlorophenylboronic acid for 489A and 172A for 50A to provide thedesired compound: MS (m/z) 446.5 [M+H]⁺.

Synthesis of(S)-1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethanamine(524C)

The title compound was prepared according to the method presented in thesynthesis of 50C substituting (S)-tert-butyl1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethylcarbamatefor 50B to provide the desired compound: MS (m/z) 346.3 [M+H]⁺.

Synthesis of(S)—N-(1-(5-(4-chlorophenyl)pyrimidin-4-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide(524D)

The title compound was prepared according to the method presented in thesynthesis of 61F substituting 287C for 61C and 524C for 61E to providethe desired compound (25 mg): ¹H NMR (400 MHz, cd₃od) δ 9.21 (s, 1H),9.06 (d, 1H), 8.52 (s, 1H), 7.41 (d, 2H), 7.14 (d, 2H), 6.94-6.61 (m,2H), 6.34 (d, 2H), 5.41 (q, 1H), 5.06 (s, 2H), 3.03 (d, 2H), 2.62-2.40(m, 4H); MS (m/z) 630.7 [M+H]⁺.

Example 525

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(4-hydroxy-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide (525)

A round bottom flask was charged(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(10 mg, 0.2 mmol), DCM (3 ml), i-PrOH (0.25 ml), and NaBH₄ (8 mg, 0.2mmol). The reaction was stirred at room temperature until done by LC/MSthen quenched with 1 N HCl and concentrated. The mixture was dissolvedin DMF, filtered, and purified by HPLC to obtain the desired compound(7.8 mg, 65%): ¹H NMR (400 MHz, cd₃od) δ 8.69 (d, 1H), 7.60 (d, 1H),7.47-7.38 (m, 2H), 7.28 (s, 1H), 7.22 (d, 1H), 6.66 (s, 1H), 6.33 (s,2H), 5.35 (s, 1H), 5.07 (s, 1H), 4.80 (s, 2H), 3.06 (t, 2H), 2.83 (d,2H), 2.56 (s, 2H), 2.41-2.30 (m, 1H); MS (m/z) 586.4 [M+H]⁺.

Example 526

Synthesis of (S)-tert-butyl(3-(2-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-1H-indol-6-yl)methylcarbamate(526)

The title compound was prepared according to the method presented in thesynthesis of 36F utilizing 36E and2-(6-((tert-butoxycarbonylamino)methyl)-1H-indol-3-yl)acetic acid toprovide 24 mg of the desired compound in a 33% yield: ¹H NMR (400 MHz,dmso) δ 10.70 (s, 1H), 8.65-8.61 (m, 1H), 8.53 (d, 1H), 7.53 (dd, 1H),7.41-7.32 (m, 3H), 7.27 (s, 1H), 7.21 (dd, 3H), 7.13 (s, 1H), 6.98 (s,1H), 6.92 (t, 1H), 6.76 (d, 1H), 6.42 (d, 2H), 5.19-5.08 (m, 1H), 4.12(d, 2H), 3.44 (d, 2H), 2.95-2.88 (m, 2H), 1.36 (s, 9H); MS (m/z) 631.7[M+H]⁺.

Example 527

Synthesis of methyl 2-oxo-2-(6-(trifluoromethyl)-1H-indol-3-yl)acetatehydrochloride (527B)

The title compound was prepared according to the method presented inExample 54 substituting 6-(trifluoromethyl)-1H-indole for 54C to providethe desired compound: MS (m/z) 271.9 [M+H]⁺.

Synthesis of methyl 2-(6-(trifluoromethyl)-1H-indol-3-yl)acetate (527C)

The title compound was prepared according to the method presented inExample 54 substituting methyl2-oxo-2-(6-(trifluoromethyl)-1H-indol-3-yl)acetate hydrochloride for 54Dto provide the desired compound: MS (m/z) 257.8 [M+H]⁺.

Synthesis of methyl 2-(6-(trifluoromethyl)-1H-indol-3-yl)acetic acid(527D)

The title compound was prepared according to the method presented inExample 54 substituting methyl2-(6-(trifluoromethyl)-1H-indol-3-yl)acetate for 54E to provide thedesired compound MS (m/z) 243.9 [M+H]⁺.

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(6-(trifluoromethyl)-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(527E)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and2-(6-(trifluoromethyl)-1H-indol-3-yl)acetic acid to provide 27.2 mg ofthe desired compound in a 55% yield: ¹H NMR (400 MHz, dmso) δ 11.23 (s,1H), 8.72 (d, 1H), 8.67 (dd, 1H), 7.96 (s, 1H), 7.87 (d, 1H), 7.75 (s,1H), 7.64-7.57 (m, 2H), 7.53-7.37 (m, 4H), 7.26 (d, 1H), 7.11 (d, 1H),6.87 (t, 1H), 6.49 (d, 2H), 5.17 (dd, 2H), 3.50 (dd, 2H), 2.96 (d, 2H);MS (m/z) 579.2 [M+H]⁺.

Example 529

Synthesis of(S)-tert-butyl(3-(2-(1-(3-(3-carbamoylphenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-1H-indol-5-yl)methylcarbamate(529)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and 491E to provide 20 mg of the desiredcompound in a 27% yield: ¹H NMR (400 MHz, dmso) δ 10.71 (s, 1H), 8.64(d, 1H), 8.52 (d, 1H), 7.93 (s, 1H), 7.86 (d, 1H), 7.71 (s, 1H), 7.59(d, 1H), 7.47-7.33 (m, 4H), 7.27-7.14 (m, 3H), 7.00-6.91 (m, 2H), 6.86(t, 1H), 6.41 (d, 2H), 5.22 (d, 1H), 4.10 (d, 2H), 3.45 (s, 2H), 2.94(d, 2H), 1.34 (s, 9H); MS (m/z) 640.0 [M+H]⁺.

Example 530

Synthesis of methyl 2-(5,7-difluoro-1H-indol-3-yl)-2-oxoacetatehydrochloride (530B)

The title compound was prepared according to the method presented inExample 54 substituting 5,7-difluoro-1H-indole for 54C to provide thedesired compound: MS (m/z) 240.1 [M+H]⁺.

Synthesis of methyl 2-(5,7-difluoro-1H-indol-3-yl)acetate (530C)

A flask is charged with methyl2-(5,7-difluoro-1H-indol-3-yl)-2-oxoacetate hydrochloride (750 mg, 2.7mmol), EtOH (150 ml), EtOAc (49 ml), and AcOH (1 ml). The mixture waspassed through a flow hydrogenator fitted with a 10% Pd/C cartridge (0.8ml/min, 40 bar, 100° C.). The mixture was collected into a flask chargedwith NaHCO₃. Once complete, the mixture is filtered and concentrated.The mixture was dissolved in DCM and remaining starting material isprecipitated out by the addition of hexane. The organic layer is thenconcentrated to give the desired compound (150 mg, 25%): MS (m/z) 226.1[M+H]⁺.

Synthesis of 2-(5,7-difluoro-1H-indol-3-yl)acetic acid (530D)

The title compound was prepared according to the method presented inExample 54 substituting methyl 2-(5,7-difluoro-1H-indol-3-yl)acetate for54E to provide the desired compound: MS (m/z) 212.1 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(5,7-difluoro-1H-indol-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(530E)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting 2-(5,7-difluoro-1H-indol-3-yl)acetic acidfor 54F to provide the desired compound (33 mg, 41%): ¹H NMR (400 MHz,dmso) δ 11.37 (s, 1H), 8.73-8.60 (m, 2H), 7.64 (d, 2H), 7.57 (dd, 1H),7.48 (d, 1H), 7.38 (dd, 2H), 7.33-7.21 (m, 1H), 7.14 (d, 1H), 6.98 (dd,1H), 6.84 (t, 2H), 6.50 (d, 2H), 5.13 (dd, 1H), 3.51-3.35 (m, 2H), 2.96(d, 2H); MS (m/z) 565.6 [M+H]⁺.

Example 531

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)butanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(531)

The title compound was separated from the diastereomeric mixture of 504Eby semi-preparative chiral HPLC fitted with a Chiralcel AZ-H columnrunning a 70:30 mixture of Hep:IPA to obtain the desired compound (RT7.8 minutes, 4.9 mg): ¹H NMR (400 MHz, dmso) δ 8.87 (d, 1H), 8.64 (d,1H), 7.69 (s, 2H), 7.64 (d, 1H), 7.56 (d, 1H), 7.49 (s, 1H), 7.43-7.32(m, 2H), 6.96 (s, 1H), 6.65 (d, 2H), 5.08 (d, 1H), 4.66 (s, 1H), 3.00(d, 2H), 2.39 (s, 2H), 1.94 (s, 3H), 1.57 (s, 3H), 1.53-1.42 (m, 2H),0.68 (t, 3H); MS (m/z) 630.9 [M+H]⁺.

Example 532

Synthesis of5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)butanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(532)

The title compound was separated from the diastereomeric mixture of 504Eby semi-preparative chiral HPLC fitted with a Chiralcel AZ-H columnrunning a 70:30 mixture of Hep:IPA to obtain the desired compound (RT10.1 minutes, 4.9 mg): ¹H NMR (400 MHz, dmso) δ 8.77 (d, 1H), 8.61 (d,1H), 7.66 (s, 2H), 7.61 (d, 1H), 7.54 (s, 1H), 7.50-7.43 (m, 1H),7.41-7.37 (m, 1H), 7.37-7.29 (m, 1H), 6.94 (s, 1H), 6.56 (d, 2H), 5.12(s, 1H), 4.71 (s, 1H), 2.96 (d, 2H), 2.62-2.44 (m, 2H), 2.41 (s, 2H),2.29 (s, 2H), 1.91 (s, 2H), 1.60 (s, 3H), 0.63 (t, 3H); MS (m/z) 630.9[M+H]⁺.

Example 533

Synthesis of methyl 2-(5,6-difluoro-1H-indol-3-yl)-2-oxoacetatehydrochloride (533B)

The title compound was prepared according to the method presented inExample 54 substituting 5,6-difluoro-1H-indole for 54C to provide thedesired compound: MS (m/z) 240.1 [M+H]⁺.

Synthesis of methyl 2-(5,6-difluoro-1H-indol-3-yl)acetate (533C)

The title compound was prepared according to the method presented inExample 530 substituting methyl2-(5,6-difluoro-1H-indol-3-yl)-2-oxoacetate hydrochloride for 530B toprovide the desired compound: MS (m/z) 226.0 [M+H]⁺.

Synthesis of 2-(5,6-difluoro-1H-indol-3-yl)acetic acid (533D)

The title compound was prepared according to the method presented inExample 54 substituting methyl 2-(5,6-difluoro-1H-indol-3-yl)acetate for54E to provide the desired compound: MS (m/z) 212.1 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(5,6-difluoro-1H-indol-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(533E)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting 2-(5,6-difluoro-1H-indol-3-yl)acetic acidfor 54F to provide the desired compound (35 mg, 44%): ¹H NMR (400 MHz,dmso) δ 10.92 (s, 1H), 8.71-8.62 (m, 2H), 7.64 (d, 2H), 7.60-7.56 (m,1H), 7.48 (dd, 1H), 7.38 (dd, 2H), 7.35-7.19 (m, 3H), 7.08 (d, 1H), 6.85(t, 1H), 6.50 (d, 2H), 5.13 (dd, 1H), 3.49-3.34 (m, 2H), 3.02-2.91 (m,2H); MS (m/z) 565.8 [M+H]⁺.

Example 534

Synthesis of(S)—N-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(4-methyl-1H-indol-3-yl)acetamide(534)

The title compound was prepared according to the method presented in thesynthesis of 36F utilizing 36E and 2-(4-methyl-1H-indol-3-yl)acetic acidto provide 17 mg of the desired compound in a 28% yield: ¹H NMR (400MHz, dmso) δ 10.74 (s, 1H), 8.59 (dd, 1H), 8.30 (d, 1H), 7.54 (dd, 1H),7.41 (d, 2H), 7.36 (dd, 1H), 7.21 (d, 2H), 7.09 (d, 1H), 6.95 (dd, 2H),6.88-6.81 (m, 1H), 6.57 (d, 1H), 6.41 (d, 2H), 5.17 (dd, 1H), 3.69-3.56(m, 2H), 2.92 (dd, 2H), 2.30 (s, 3H); MS (m/z) 516.8 [M+H]⁺.

Example 535

Synthesis of 2-(2,2,2-trifluoroacetyl)cyclopentane-1,3-dione (535B)

A round bottom is charged with cyclopentane-1,3-dione (2 g, 20 mmol),imidazole (1.4 g, 20 mmol), DCM (60 ml), and1-(trifluoroacetyl)imidazole (3.35 g, 20 mmol). The resulting mixturewas stirred for 3 hours and quenched with 1 M HCl. The resulting mixturewas extracted 2× DCM. The organic layer was dried over sodium sulfate,filtered, concentrated and used with no further purification to give thedesired compound (2.8 g, 70%): MS (m/z) 195.0 [M+H]⁺.

Synthesis of ethyl2-(4-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetate(535C)

A round bottom is charged with2-(2,2,2-trifluoroacetyl)cyclopentane-1,3-dione (2.8 g, 14 mmol), ethyl2-hydrazinylacetate (1.9 g, 12 mmol), H₂SO₄ (0.3 ml), and EtOH (15 ml).The resulting mixture was stirred at reflux overnight. The mixture wasconcentrated and diluted with EtOAc and aq. NaHCO₃. The organic layerwas dried over sodium sulfate, filtered, concentrated and purified byflash chromatography to give the desired compound (2.6 g, 67%): MS (m/z)277.1 [M+H]⁺.

Synthesis of ethyl2-(3-(trifluoromethyl)-5,6-dihydro-1H-spiro[cyclopenta[c]pyrazole-4,2′-[1,3]dithiolane]-1-yl)acetate(535D)

A round bottom is charged with ethyl2-(4-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetate(300 mg, 1 mmol), DCM (2 ml), ethane-1,2-dithiol (0.1 ml, 1.2 mmol),Boron trifluoride etherate (0.13 ml, 1.1 mmol), and AcOH (1 ml). Theresulting mixture was stirred overnight. The mixture was diluted withH₂O and extracted 2× DCM. The organic layers were dried over sodiumsulfate, filtered, concentrated and was used without furtherpurification to give the desired compound (320 mg, 91%): MS (m/z) 353.3[M+H]⁺.

Synthesis of ethyl2-(4,4-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetate (535E)

A round bottom is charged with ethyl2-(3-(trifluoromethyl)-5,6-dihydro-1H-spiro[cyclopenta[c]pyrazole-4,2′-[1,3]dithiolane]-1-yl)acetate(100 mg, 0.3 mmol), DCM (1 ml), and HF/Py (1 ml). The resulting mixturewas cooled to −45° C. and then a mixture of NIS (158 mg, 0.7 mmol) andDCM (1 ml) was added to the reaction. The mixture was stirred allowingto slowly warm to −30° C. over 3 hours. The reaction was quenched withaq. NaHCO₃ and extracted with DCM. The organic layer was washed withwater, dried over sodium sulfate, filtered, concentrated and purified byflash chromatography to give the desired compound (35 mg, 42%): MS (m/z)299.1 [M+H]⁺.

Synthesis of2-(4,4-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)aceticacid (535F)

The title compound was prepared according to the method presented inExample 491 substituting ethyl2-(4,4-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetate for 491D to provide the desired compound: MS (m/z) 271.0[M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(4,4-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(535G)

The title compound was prepared according to the method presented in thesynthesis of 54G utilizing 54B and2-(4,4-difluoro-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)aceticacid to provide 20 mg of the desired compound in a 24% yield: ¹H NMR(400 MHz, cd₃od) δ 8.69 (d, 1H), 7.58 (d, 1H), 7.43 (s, 1H), 7.39 (dd,1H), 7.33-7.26 (m, 1H), 7.25-7.17 (m, 1H), 6.65 (s, 1H), 6.32 (d, 2H),5.39-5.31 (m, 1H), 4.87 (s, 2H), 3.05 (ddd, 5H), 2.87 (s, 2H); MS (m/z)624.2 [M+H]⁺.

Example 536

Synthesis of 2,5-dimethyl-4-nitrophenol (536B)

A round bottom was charged with 2,5-dimethylphenol (2 g, 16.4 mmol),H₂SO₄ (0.7 ml), AcOH (5 ml), and cool the reaction to 0° C. To thecooled stirring reaction slowly add sodium nitrate (1.15 g, 14 mmol)dissolved in H₂O (3.3 ml) keeping the temperature between 8-10° C. After10 minutes add ice and filter off solid. The solid was air dried for 30minutes after which it was slowly added to a RB with a solution of 70%nitric acid (1.65 ml) and H₂O (5 ml) heated to 50° C. The reaction wasallowed to stir overnight. Water was added and the solution wasfiltered. The cake was rinsed with water then dissolved in EtOAc, driedover sodium sulfate, filtered, concentrated. The mixture was dissolvedin DCM followed by hexane to precipitate out solid, filtered, and driedunder vacuum to give the desired compound (1.5 g, 56%): ¹H NMR (400 MHz,cdcl₃) δ 7.92 (s, 1H), 7.24 (s, 1H), 6.65 (s, 1H), 5.26 (s, 1H), 2.55(s, 3H), 2.25 (s, 3H).

Synthesis of 1-(benzyloxy)-2,5-dimethyl-4-nitrobenzene (536C)

A round bottom was charged with 2,5-dimethyl-4-nitrophenol (1.5 g, 9mmol), DMF (11 ml), K₂CO₃ (1.3 g, 9.1 mmol), and BnCl (1.5 ml, 12 mmol).The mixture was stirred at RT for 2 hours. The reaction was diluted withH₂O and extracted 2× with EtOAc. The organic layer was dried over sodiumsulfate, filtered, concentrated and purified by flash chromatography togive the desired compound (1.5 mg, 65%): MS (m/z) 258.0 [M+H]⁺.

Synthesis of 1-(5-(benzyloxy)-4-methyl-2-nitrostyryl)pyrrolidine (536D)

A round bottom was charged with1-(benzyloxy)-2,5-dimethyl-4-nitrobenzene (1.5 g, 5.8 mmol), DMF (5 ml),DMFDMA (1.2 ml, 9 mmol) and pyrrolidine (0.73 ml, 9 mmol). The resultingmixture was heated to 110° C. for 3 hours. The mixture was concentratedto 1/3 volume then diluted with DCM then the desired compound wasprecipitated by the addition of hexane. The solid was filtered and driedunder vacuum to give the desired compound (1.4 g, 71%).

Synthesis of methyl 5-(benzyloxy)-6-methyl-1H-indole (536E)

A round bottom was charged with1-(5-(benzyloxy)-4-methyl-2-nitrostyryl)pyrrolidine (1.1 g, 3.4 mmol),dioxane (38 ml), Pd/C (400 mg), H2NaO2P•H2O (800 mg, 7.5 mmol), and H₂O(3.8 ml). The resulting mixture was stirred at 65° C. until done asindicated by LC/MS. The reaction mixture was cooled to RT and filteredover a plug of celite, rinsing with ethyl acetate. The layers werepartitioned and the organic layer was dried over sodium sulfate,filtered, concentrated and purified by flash chromatography to give thedesired compound as a white solid (540 mg, 67%): MS (m/z) 238.0 [M+H]⁺.

Synthesis of methyl2-(5-(benzyloxy)-6-methyl-1H-indol-3-yl)-2-oxoacetate hydrochloride(536F)

The title compound was prepared according to the method presented inExample 54 substituting 5-(benzyloxy)-6-methyl-1H-indole for 54C toprovide the desired compound: MS (m/z) 323.9 [M+H]⁺.

Synthesis of methyl 2-(5-(benzyloxy)-6-methyl-1H-indol-3-yl)acetate(536G)

The title compound was prepared according to the method presented inExample 54 substituting methyl2-(5-(benzyloxy)-6-methyl-1H-indol-3-yl)-2-oxoacetate hydrochloride for54D to provide the desired compound: MS (m/z) 310.1 [M+H]⁺.

Synthesis of 2-(5-(benzyloxy)-6-methyl-1H-indol-3-yl)acetic acid (536H)

The title compound was prepared according to the method presented inExample 54 substituting methyl2-(5-(benzyloxy)-6-methyl-1H-indol-3-yl)acetate for 54E to provide thedesired compound: MS (m/z) 296.0 [M+H]⁺.

Synthesis of(S)-3-(2-(1-(2-(5-(benzyloxy)-6-methyl-1H-indol-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(536I)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and2-(5-(benzyloxy)-6-methyl-1H-indol-3-yl)acetic acid to provide 35 mg ofthe desired compound in a 40% yield: ¹H NMR (400 MHz, dmso) δ 10.51 (s,1H), 8.59 (d, 1H), 8.47 (d, 1H), 7.94 (s, 1H), 7.86 (d, 1H), 7.71 (s,1H), 7.58 (d, 1H), 7.43 (t, 3H), 7.40-7.33 (m, 5H), 7.29 (d, 11H), 7.05(d, 2H), 6.89 (s, 1H), 6.83 (t, 1H), 6.39 (d, 2H), 5.23 (d, 1H), 4.93(s, 2H), 3.44 (s, 2H), 2.92 (d, 2H), 2.22 (s, 3H); MS (m/z) 631.4[M+H]⁺.

Example 537

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(2-isopropyl-1H-imidazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(537)

The title compound was prepared according to the method presented inExample 56 substituting 2-isopropyl-1H-imidazole for 1H-benzo[g]indoleto provide the desired compound (14 mg, 38%): ¹H NMR (400 MHz, dmso) δ9.16 (d, 1H), 8.70 (d, 1H), 7.65 (dd, 3H), 7.53 (d, 2H), 7.43 (dd, 1H),7.38 (d, 2H), 7.37-7.28 (m, 1H), 6.97 (t, 1H), 6.64 (d, 2H), 5.16 (d,1H), 4.87 (q, 2H), 3.04 (dt, 2H), 2.86-2.74 (m, 1H), 1.07 (dd, 6H); MS(m/z) 522.7 [M+H]⁺.

Example 538

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3,5-diisopropyl-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(538)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting 3,5-diisopropyl-1H-pyrazole for1H-benzo[g]indole to provide the desired compound (8 mg, 20%): ¹H NMR(400 MHz, dmso) δ 8.63 (d, 1H), 8.47 (d, 1H), 7.63 (dd, 3H), 7.48 (d,1H), 7.40 (dd, 2H), 7.36-7.26 (m, 1H), 6.92 (s, 1H), 6.53 (d, 2H), 5.82(s, 1H), 5.17 (d, 1H), 4.57 (s, 2H), 2.96 (dd, 2H), 2.77-2.68 (m, 1H),2.67-2.53 (m, 1H), 1.10 (d, 6H), 0.98 (d, 6H); MS (m/z) 564.4 [M+H]⁺.

Example 539

Synthesisof(S)-2-(3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(3-(4-(morpholinosulfonyl)phenyl)pyridin-2-yl)ethyl)acetamide(539)

The title compound was prepared according to the method presented in thesynthesis of 512C substituting 4-(morpholinosulfonyl)phenylboronic acidfor5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridineto provide the desired compound (21 mg, 17%): ¹H NMR (400 MHz, dmso) δ9.09 (d, 1H), 8.72 (dd, 1H), 7.70 (d, 2H), 7.61 (dd, 1H), 7.49-7.35 (m,3H), 7.15 (d, 1H), 7.08-6.80 (m, 4H), 6.34 (d, 2H), 5.14 (dd, 1H), 4.99(s, 2H), 3.66-3.57 (m, 4H), 2.95 (d, 2H), 2.88 (d, 4H); MS (m/z) 668.2[M+H]⁺.

Examples 540 and 571

Synthesis of ethyl2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)-4,4,4-trifluorobutanoate(540C)

The title compound was prepared according to the method presented inExample 478 substituting 540A for 478A and 540B for 478B to provide thedesired compound: MS (m/z) 315.5 [M+H]⁺.

Synthesis of2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)-4,4,4-trifluorobutanoic acid(540D)

The title compound was prepared according to the method presented inExample 478 ethyl2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)-4,4,4-trifluorobutanoate for478C to provide the desired compound: MS (m/z) 287.3 [M+H]⁺.

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)-4,4,4-trifluorobutanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(540E and 571)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)-4,4,4-trifluorobutanoic acidfor 2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid to provide thedesired compounds (540E, the first peak off HPLC, 7 mg, 8%; 571, thesecond peak off HPLC, 12 mg, 14%): 540E ¹H NMR (400 MHz, dmso) δ 8.80(d, 1H), 8.66 (d, 1H), 8.59-8.50 (m, 1H), 7.62 (s, 2H), 7.55 (d, 1H),7.51 (s, 1H), 7.42 (s, 1H), 7.39 (d, 1H), 7.31 (s, 1H), 7.21 (d, 2H),6.75 (s, 1H), 6.28 (d, 2H), 5.83-5.73 (m, 1H), 5.03 (d, 1H), 3.42-3.31(m, 2H), 3.12 (s, 2H), 2.31 (s, 3H), 2.28 (s, 3H); MS (m/z) 640.4[M+H]⁺; 571 MS (m/z) 640.4 [M+H]⁺.

Example 541 Synthesis of(S)-2-(3-acetyl-1H-indol-1-yl)-N-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide(541)

The title compound was prepared according to the method presented in thesynthesis of 36F utilizing 36E and 2-(3-acetyl-1H-indol-1-yl)acetic acidto provide 16.2 mg of the desired compound in a 25% yield: ¹H NMR (400MHz, dmso) δ 9.13 (d, 1H), 8.71 (dd, 1H), 8.14 (s, 1H), 8.10 (d, 1H),7.57 (dd, 1H), 7.40 (dd, 3H), 7.21 (d, 2H), 7.17-7.05 (m, 3H), 6.99 (t,1H), 6.50 (d, 2H), 5.21-5.10 (m, 1H), 4.88 (s, 2H), 2.99 (d, 2H), 2.36(s, 3H); MS (m/z) 544.7 [M+H]⁺.

Example 542

Synthesis of(S)-5-(2-(1-(2-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(542)

The title compound was prepared according to the method presented inExample 56 substituting 3,5-bis(trifluoromethyl)-1H-pyrazole for1H-benzo[g]indole and heating to 95° C. to provide the desired compound(4 mg, 10%): ¹H NMR (400 MHz, dmso) δ 9.05 (d, 1H), 8.68 (d, 1H), 7.63(dd, 3H), 7.47 (d, 2H), 7.45-7.41 (m, 1H), 7.40 (s, 1H), 7.35-7.27 (m,1H), 6.91 (t, 1H), 6.57 (d, 2H), 5.14 (d, 1H), 5.09-4.95 (m, 2H),3.08-2.90 (m, 2H); MS (m/z) 616.5 [M+H]⁺.

Example 543

Synthesis of5-(2-((1S)-1-(2-(3-acetyl-1H-indol-1-yl)butanamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(543)

The title compound was separated from the diastereomeric mixture of 554by semi-preparative chiral HPLC fitted with a Chiralpak IA columnrunning a 70:30 mixture of Hep:IPA to obtain the desired compound (RT6.4 minutes, 11 mg): ¹H NMR (400 MHz, dmso) δ 9.21 (d, 1H), 8.61 (d,1H), 8.23 (s, 11H), 8.10 (d, 1H), 7.66 (d, 2H), 7.51 (dd, 3H), 7.33 (dd,2H), 7.16 (dt, 3H), 6.97 (s, 1H), 6.65 (d, 2H), 5.14 (d, 1H), 5.04 (t,1H), 3.04 (d, 2H), 2.37 (s, 3H), 2.04-1.89 (m, 2H), 0.65 (t, 3H); MS(m/z) 599.6 [M+H]⁺.

Example 544

Synthesis of5-(2-((1S)-1-(2-(3-acetyl-1H-indol-1-yl)butanamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(544)

The title compound was separated from the diastereomeric mixture of 554by semi-preparative chiral HPLC fitted with a Chiralpak IA columnrunning a 70:30 mixture of Hep:IPA to obtain the desired compound (RT9.5 minutes, 12 mg): ¹H NMR (400 MHz, dmso) δ 9.24 (d, 1H), 8.69 (s,1H), 8.26 (s, 1H), 8.09 (s, 1H), 7.64 (d, 3H), 7.56-7.37 (m, 4H), 7.32(d, 1H), 7.13 (d, 2H), 6.82 (s, 1H), 6.56 (d, 2H), 5.07 (s, 2H), 2.99(d, 2H), 2.38 (s, 3H), 2.01 (s, 2H), 0.75 (t, 3H); MS (m/z) 599.6[M+H]⁺.

Example 545

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(6-methyl-1H-indol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(545)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting 6-methyl-1H-indole for 1H-benzo[g]indoleto provide the desired compound (7 mg, 18%): ¹H NMR (400 MHz, dmso) δ8.89 (d, 1H), 8.68 (d, 1H), 7.67-7.56 (m, 3H), 7.48 (d, 1H), 7.40 (dd,2H), 7.34 (dd, 1H), 7.30-7.22 (m, 1H), 7.05 (d, 1H), 6.93 (t, 1H), 6.85(s, 1H), 6.77 (d, 1H), 6.60 (d, 2H), 6.25 (d, 1H), 5.13 (d, 1H), 4.71(s, 2H), 3.01 (d, 2H), 2.29 (s, 3H); MS (m/z) 543.4 [M+H]⁺.

Example 546

Synthesis of ethyl 2-(4,6-difluoro-1H-indol-1-yl)acetate

The title compound was prepared according to the method presented inExample 478 substituting ethyl 2-bromoacetate for 478B and4,6-difluoro-1H-indole for 478A to provide the desired compound.

Synthesis of 2-(4,6-difluoro-1H-indol-1-yl)acetic acid (546B)

The title compound was prepared according to the method presented inExample 478 substituting ethyl 2-(4,6-difluoro-1H-indol-1-yl)acetate for478C to provide the desired compound: MS (m/z) 212.2 [M+H]⁺.

Synthesis of(S)-3-(2-(1-(2-(4,6-difluoro-1H-indol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(546C)

The title compound was prepared according to the method presented in thesynthesis of 50C substituting 2-(4,6-difluoro-1H-indol-1-yl)acetic acidfor 2-(5-fluoro-1H-indol-3-yl)acetic acid to provide the desiredcompound (23 mg, 36%): ¹H NMR (400 MHz, dmso) δ 8.96 (d, 1H), 8.72-8.66(m, 1H), 7.93 (s, 1H), 7.88 (d, 1H), 7.73 (s, 1H), 7.64 (dd, 1H),7.49-7.36 (m, 4H), 7.17 (d, 1H), 6.88 (t, 1H), 6.82 (d, 1H), 6.76 (t,1H), 6.53 (d, 2H), 6.39 (d, 1H), 5.17 (dd, 1H), 4.77 (s, 2H), 2.99 (d,2H). MS (m/z) 547.6 [M+H]⁺.

Example 547

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-methyl-1H-indol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(547)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting 5-methyl-1H-indole for 1H-benzo[g]indoleto provide the desired compound (7 mg, 18%): ¹H NMR (400 MHz, dmso) δ8.89 (d, 1H), 8.68 (d, 1H), 7.60 (dd, 3H), 7.48 (d, 1H), 7.40 (dd, 2H),7.26 (t, 1H), 7.23 (s, 1H), 7.07 (d, 1H), 6.95 (d, 1H), 6.90 (d, 1H),6.79 (d, 1H), 6.61 (d, 2H), 6.21 (d, 1H), 5.12 (d, 1H), 4.70 (s, 2H),3.01 (d, 2H), 2.30 (s, 3H); MS (m/z) 543.4 [M+H]⁺.

Example 548

Synthesis of (S)-tert-butyl2-(3,5-difluorophenyl)-1-(3-(2-oxoindolin-5-yl)pyridin-2-yl)ethylcarbamate(548B)

The title compound was prepared according to the method presented in thesynthesis of 489B substituting 5-bromoindolin-2-one for 489A to providethe desired compound: MS (m/z) 466.3 [M+H]⁺.

Synthesisof(S)-5-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)indolin-2-one(548C)

The title compound was prepared according to the method presented in thesynthesis of 50C substituting (S)-tert-butyl2-(3,5-difluorophenyl)-1-(3-(2-oxoindolin-5-yl)pyridin-2-yl)ethylcarbamatefor 50B to provide the desired compound: MS (m/z) 366.1 [M+H]⁺.

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(3-(2-oxoindolin-5-yl)pyridin-2-yl)ethyl)acetamide(548D)

The title compound was prepared according to the method presented in thesynthesis of 61F substituting 287C for 61C and 548C for 61E to providethe desired compound (13 mg): ¹H NMR (400 MHz, cd₃od) δ 8.64 (d, 1H),7.63-7.55 (m, 1H), 7.40 (dd, 1H), 6.93 (d, 1H), 6.87 (d, 1H), 6.80 (s,1H), 6.74-6.63 (m, 1H), 6.28 (d, 2H), 5.55-5.44 (m, 1H), 5.08 (s, 2H),3.49 (q, 3H), 3.02 (dd, 2H), 2.64-2.42 (m, 4H); MS (m/z) 650.4 [M+H]⁺.

Example 549

Synthesis of(S)-2-(6-(aminomethyl)-1H-indol-3-yl)-N-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)acetamide(549)

The title compound was prepared according to the method presented in thesynthesis of 557 utilizing (S)-tert-butyl(3-(2-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-1H-indol-6-yl)methylcarbamateto provide 18 mg of the desired compound in a 99% yield: ¹H NMR (400MHz, dmso) δ 10.97 (s, 1H), 8.65 (dd, 1H), 8.60 (d, 1H), 8.00 (s, 2H),7.53 (dd, 1H), 7.46-7.30 (m, 5H), 7.21 (d, 2H), 7.09 (s, 1H), 6.94 (t,2H), 6.44 (d, 2H), 5.13 (dd, 2H), 4.04 (d, 3H), 3.56-3.40 (m, 3H),3.00-2.86 (m, 2H); MS (m/z) 531.4 [M+H]⁺.

Example 550

Synthesis of(S)-5-(2-(1-(2-(4,6-dichloro-1H-indazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(550)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting 4,6-dichloro-1H-indazole for1H-benzo[g]indole to provide the desired compound (4 mg, 10%): ¹H NMR(400 MHz, dmso) δ 9.11 (d, 1H), 8.69 (d, 1H), 8.40 (s, 1H), 7.67-7.56(m, 4H), 7.46-7.37 (m, 3H), 7.34-7.24 (m, 1H), 7.18 (d, 1H), 6.90 (s,1H), 6.51 (d, 2H), 5.22-5.05 (m, 3H), 3.00 (d, 2H); MS (m/z) 598.6[M+H]⁺.

Example 551

Synthesis of(S)-5-(2-(1-(2-(4,4-difluoro-6-oxo-3-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(551)

A round bottom is charged with(S)-5-(2-(1-(2-(4,4-difluoro-3-(trifluoromethyl)-5,6dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(9 mg, 0.14 mmol), AcOH (2 ml), and CrO₃ (22 mg, 0.2 mmol). The mixturewas stirred for 1.5 days. The reaction was concentrated then dilutedwith DMF, H₂O, and TFA, filtered and purified by HPLC to give thedesired compound (2 mg, 24%): ¹H NMR (400 MHz, cd₃od) δ 8.70 (s, 1H),7.56 (d, 1H), 7.39 (dd, 2H), 7.29 (s, 1H), 7.23-7.15 (m, 1H), 6.64 (t,1H), 6.29 (d, 2H), 5.38-5.31 (m, 1H), 5.10 (s, 2H), 3.61 (td, 1H), 3.46(d, 1H), 3.14-3.03 (m, 3H); MS (m/z) 638.2 [M+H]⁺.

Example 552

Synthesis of5-(2-((1S)-1-(2-cyclopentyl-2-phenylacetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(552)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting 2-cyclopentyl-2-phenylacetic acid for 54Fto provide the desired compound (the first peak off HPLC, 13 mg, 18%):¹H NMR (400 MHz, dmso) δ 8.72-8.62 (m, 2H), 7.67 (d, 2H), 7.57 (dd, 1H),7.45 (d, 2H), 7.37 (dd, 1H), 7.35-7.25 (m, 1H), 7.15 (ddd, 5H), 6.77 (t,1H), 6.43 (d, 2H), 4.97 (dd, 1H), 3.28 (d, 1H), 2.89 (dd, 2H), 2.37 (s,1H), 1.56-1.19 (m, 6H), 1.01 (s, 1H), 0.83 (d, 1H); MS (m/z) 558.6[M+H]⁺.

Example 553

Synthesis of(S)-5-(2-(1-(2-(3,5-bis(difluoromethyl)-4-vinyl-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(533)

A 40 ml vial was charged with 555C (100 mg, 0.15 mmol), DMF (1 ml), DME(4 ml), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.1 ml),Pd(OAc)₂ (10 mg, 0.01 mmol), XPhos (14 mg, 0.02 mmol) and 2 N K₃PO₄ (0.3ml). Heat the stirring mixture overnight at 86° C. Allow the reaction tocool then dilute with H₂O and extract 2× EtOAc. The combined organiclayers were washed with brine then dried over sodium sulfate,concentrated, and purified by HPLC to give 54 mg of the desiredcompound. The yield was 60%: ¹H NMR (400 MHz, cd₃od) δ 8.69 (d, 1H),7.57 (dd, 1H), 7.42-7.35 (m, 2H), 7.28 (s, 1H), 7.24-7.17 (m, 1H),7.08-6.74 (m, 3H), 6.72 (s, 1H), 6.70-6.59 (m, 2H), 6.30 (d, 2H), 5.49(dd, 2H), 5.38-5.29 (m, 1H), 5.04 (s, 2H), 3.12-2.98 (m, 2H), 1.21 (t,2H); MS (m/z) 605.1 [M+H]⁺.

Example 554

Synthesis of5-(2-((1S)-1-(2-(3-acetyl-1H-indol-1-yl)butanamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(554)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting 2-(3-acetyl-1H-indol-1-yl)butanoic acidfor 54F to provide the desired compound (47 mg, 56%): MS (m/z) 599.6[M+H]⁺.

Example 155

Synthesis of 4-bromo-3,5-bis(difluoromethyl)-1H-pyrazole (555B)

A round bottom flask was charged with3,5-bis(difluoromethyl)-1H-pyrazole (5.3 g, 31 mmol) and CCl₄ (50 ml),NBS (8.1 g, 47 mmol), and lastly AIBN (5 mg). The mixture was stirred at90° C. over night. After cooling the mixture was filtered andconcentrated and purified by flash chromatography to yield 3.3 g of thedesired compound in a yield of 43%. MS (m/z) 247.0 [M+H]⁺.

Synthesis of(S)-5-(2-(1-(2-(4-bromo-3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(555C)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting4-bromo-3,5-bis(difluoromethyl)-1H-pyrazole for 1H-benzo[g]indole toprovide the desired compound (780 mg, 68%): ¹H NMR (400 MHz, dmso) δ9.07 (d, 1H), 8.68 (d, 1H), 7.70-7.57 (m, 3H), 7.45-7.36 (m, 3H), 7.31(d, 1H), 7.10 (s, 1H), 7.01 (d, 1H), 6.88 (d, 2H), 6.51 (d, 2H), 5.12(s, 1H), 5.03 (s, 2H), 2.98 (d, 2H); MS (m/z) 658.4 [M+H]⁺.

Example 556

Synthesis of(S)-3-(2-(1-(2-(5-(aminomethyl)-1H-indol-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(556)

The title compound was prepared according to the method presented in thesynthesis of 557 utilizing 529 to provide 14 mg of the desired compoundin a 99% yield: ¹H NMR (400 MHz, dmso) δ 10.92 (s, 1H), 8.64 (dd, 1H),8.55 (d, 1H), 7.96 (s, 3H), 7.87 (d, 1H), 7.74 (s, 1H), 7.61 (dd, 1H),7.48-7.35 (m, 5H), 7.32 (d, 1H), 7.13-7.04 (m, 2H), 6.87 (t, 1H), 6.46(d, 2H), 5.25-5.13 (m, 1H), 3.98 (d, 2H), 3.47 (d, 2H), 2.95 (d, 2H); MS(m/z) 540.1 [M+H]⁺.

Examples 558 and 586

Synthesis of ethyl 2-(2-isopropyl-1H-imidazol-1-yl)butanoate

The title compound was prepared according to the method presented inExample 478 substituting 504B for 478B to provide the desired compound:MS (m/z) 225.2 [M+H]⁺.

Synthesis of 2-(2-isopropyl-1H-imidazol-1-yl)butanoic acid (558A)

A flask is charged ethyl 2-(2-isopropyl-1H-imidazol-1-yl)butanoate (1 g,4.5 mmol), THF (5 ml) and HCl (2 ml). The reaction was stirred at refluxfor 2 hours. The mixture was concentrated

The residue was diluted with EtOAc and concentrated to give the desiredcompound which was used crude in the next reaction: MS (m/z) 225.2[M+H]⁺.

Synthesis of5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(2-isopropyl-1H-imidazol-1-yl)butanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(586 and 558B)

The title compounds were prepared according to the method presented inthe synthesis of 54G substituting2-(2-isopropyl-1H-imidazol-1-yl)butanoic acid for2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid to provide the desiredcompounds (586, first peak off of HPLC, 4 mg, 5%; 558B, second peak offof HPLC, 6 mg, 8%): 586 ¹H NMR (400 MHz, dmso) δ 9.27 (d, 1H), 8.68 (d,1H), 7.66 (dd, 3H), 7.57-7.53 (m, 2H), 7.42 (ddd, 4H), 6.91 (t, 1H),6.58 (d, 2H), 5.12 (d, 1H), 4.99 (s, 1H), 3.33-3.19 (m, 1H), 3.10-2.89(m, 2H), 1.89 (dd, 2H), 1.25 (d, 3H), 1.07 (d, 3H), 0.70 (t, 3H); MS(m/z) 550.6 [M+H]⁺. 558C ¹H NMR (400 MHz, dmso) δ 9.26 (d, 1H), 8.63 (d,1H), 7.61 (ddd, 5H), 7.49 (d, 1H), 7.42-7.28 (m, 3H), 6.98 (t, 1H), 6.62(d, 2H), 5.13 (d, 1H), 4.97 (d, 1H), 3.30-3.17 (m, 1H), 3.02 (d, 2H),1.89 (dd, 2H), 1.27 (d, 3H), 0.94 (d, 3H), 0.63 (t, 3H); MS (m/z) 550.6[M+H]⁺.

Example 559

Synthesis of (S)-tert-butyl2-(3,5-difluorophenyl)-1-(3-(1-oxo-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)ethylcarbamate(559B)

The title compound was prepared according to the method presented in thesynthesis of 489B substituting 7-bromoisoquinolin-1(2H)-one for 489A toprovide the desired compound: MS (m/z) 478.3 [M+H]⁺.

(S)-7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)isoquinolin-1(2H)-one(559C)

The title compound was prepared according to the method presented in thesynthesis of 50C substituting (S)-tert-butyl2-(3,5-difluorophenyl)-1-(3-(1-oxo-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)ethylcarbamatefor 50B to provide the desired compound: MS (m/z) 378.5 [M+H]⁺.

Synthesis of(S)-2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)-N-(2-(3,5-difluorophenyl)-1-(3-(1-oxo-1,2-dihydroisoquinolin-7-yl)pyridin-2-yl)ethyl)acetamide(559D)

The title compound was prepared according to the method presented in thesynthesis of 61F substituting 287C for 61C and 559C for 61E to providethe desired compound (27 mg): ¹H NMR (400 MHz, cd₃od) δ 8.72 (dd, 1H),7.78 (s, 1H), 7.67 (ddd, 3H), 7.47 (dd, 1H), 7.20 (d, 1H), 6.86 (d, 1H),6.73-6.55 (m, 2H), 6.23 (d, 2H), 5.41 (t, 1H), 5.08 (s, 2H), 3.04 (d,2H), 2.64-2.36 (m, 4H); MS (m/z) 662.6 [M+H]⁺.

Example 560

Synthesis of(S)-3-(2-(5-amino-1H-indol-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(560)

The title compound was prepared according to the method presented in thesynthesis of 491F utilizing 496B to provide 8 mg of the desired compoundin a 80% yield: ¹H NMR (400 MHz, dmso) δ 11.11 (s, 1H), 9.73 (s, 2H),8.64 (dd, 2H), 7.99 (s, 1H), 7.86 (d, 1H), 7.72 (s, 1H), 7.60 (d, 1H),7.40 (dt, 5H), 7.15 (s, 1H), 6.97 (d, 1H), 6.83 (t, 1H), 6.42 (d, 2H),5.17 (d, 1H), 3.48 (dd, 3H), 2.95 (s, 2H); MS (m/z) 526.3 [M+H]⁺.

Example 561

Synthesis of2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (561A)

The title compound was prepared according to the method presented in thesynthesis of 122F in Example 122 utilizing 181A.

Synthesis of5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(561B)

The title compound was prepared according to the method presented in thesynthesis of Example 54 utilizing 54B and 561A. MS (m/z) 559.4 [M+H]⁺.MS (m/z) 614.8 [M+H]⁺.

Example 562

Synthesis of(S)-5-(2-(1-(2-(4-cyclopropyl-3,5-bis(difluoromethyl)-1H-pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide (562)

A 40 ml vial was charged with 555C (100 mg, 0.15 mmol), DMF (0.5 ml), To(4 ml), cyclopropylboronic acid (60 mg, 0.7 mmol), Pd(OAc)₂ (10 mg, 0.01mmol), Cy₃P (8 mg, 0.02 mmol), and K₃PO₄ (50 mg, 0.3 mmol) dissolved inwater (0.2 ml). Heat the stirring mixture overnight at 110° C. Allow thereaction to cool then dilute with H₂O and extract 2× EtOAc. The combinedorganic layers were washed with brine then dried over sodium sulfate,concentrated, and purified by HPLC to give 7 mg of the desired compound.The yield was 8%: ¹H NMR (400 MHz, cd₃od) δ 8.68 (d, 1H), 7.57 (d, 1H),7.39 (dd, 2H), 7.29 (s, 1H), 7.25-7.15 (m, 1H), 7.04 (s, 1H), 6.90 (d,1H), 6.75 (s, 1H), 6.63 (d, 2H), 6.29 (d, 2H), 5.39-5.27 (m, 1H), 4.98(s, 2H), 3.05 (dd, 3H), 1.69 (s, 1H), 0.92 (d, 2H), 0.63 (d, 2H); MS(m/z) 620.2 [M+H]⁺.

Example 563

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3,4-dihydro-1H-carbazol-9(2H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(563)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting 2-(3,4-dihydro-1H-carbazol-9(2H)-yl)aceticacid for 54F to provide the desired compound (36 mg, 44%): ¹H NMR (400MHz, dmso) δ 10.86 (s, 1H), 8.69 (d, 2H), 7.65-7.51 (m, 5H), 7.39 (t,2H), 7.24 (dd, 1H), 7.15-7.07 (m, 2H), 6.93-6.75 (m, 2H), 6.48 (d, 2H),5.10 (d, 1H), 3.80-3.50 (m, 6H), 3.43 (s, 2H), 2.96 (t, 3H); MS (m/z)583.7 [M+H]⁺.

Example 564 Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(564)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)acetic acid for 54F to providethe desired compound (15 mg, 25%): ¹H NMR (400 MHz, dmso) δ 9.28 (d,1H), 9.17 (s, 1H), 8.72 (d, 1H), 7.63 (d, 3H), 7.54 (s, 1H), 7.49 (d,1H), 7.43 (dd, 1H), 7.38 (s, 1H), 7.33-7.24 (m, 1H), 7.18 (s, 1H), 6.92(s, 1H), 6.59 (d, 2H), 5.16 (d, 1H), 5.10 (s, 2H), 3.04 (d, 2H), 2.33(s, 3H), 2.29 (s, 3H); MS (m/z) 558.7 [M+H]⁺.

Example 565

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)butanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(565)

The title compound was prepared according to the method presented in thesynthesis of 483D utilizing 483C and 4-(trifluoromethyl)-1H-pyrazole toprovide 16 mg (the first peak off HPLC) of the desired compound in a 29%yield: ¹H NMR (400 MHz, dmso) δ 9.03 (d, 1H), 8.63 (d, 1H), 8.27 (s,1H), 7.78 (s, 1H), 7.68 (d, 2H), 7.61 (dd, 1H), 7.53 (d, 1H), 7.43 (s,1H), 7.41-7.37 (m, 1H), 7.34-7.27 (m, 1H), 6.95 (t, 1H), 6.62 (d, 2H),5.13 (d, 1H), 4.92 (t, 1H), 2.98 (d, 2H), 1.86-1.74 (m, 2H), 0.57 (t,3H); MS (m/z) 576.6 [M+H]⁺.

Example 566

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)butanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(566)

The title compound was prepared according to the method presented in thesynthesis of 483D utilizing 483C and 4-(trifluoromethyl)-1H-pyrazole toprovide 22 mg (the second peak off HPLC) of the desired compound in a40% yield: ¹H NMR (400 MHz, dmso) δ 8.99 (d, 1H), 8.66 (d, 1H), 8.26 (s,1H), 7.78 (s, 1H), 7.65 (s, 2H), 7.61-7.57 (m, 1H), 7.47-7.37 (m, 3H),7.36-7.27 (m, 1H), 6.84 (t, 1H), 6.46 (d, 2H), 5.10 (d, 1H), 4.93 (t,1H), 2.97 (d, 2H), 1.94-1.82 (m, 2H), 0.67 (t, 3H); MS (m/z) 576.6[M+H]⁺.

Example 567

Synthesis of(S)-5-(2-(1-(2-(3-cyclohexenyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(567)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting2-(3-cyclohexenyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acidfor 54F to provide the desired compound (29 mg, 57%): ¹H NMR (400 MHz,dmso) δ 9.01 (d, 1H), 8.70 (d, 1H), 7.69-7.57 (m, 3H), 7.49 (d, 1H),7.42 (dd, 2H), 7.33-7.23 (m, 1H), 7.02-6.93 (m, 3H), 6.89 (dt, 1H), 6.60(t, 3H), 5.80 (s, 1H), 5.16 (dd, 1H), 4.37 (dd, 2H), 3.02 (d, 2H), 2.20(d, 4H), 1.70 (d, 2H), 1.61 (d, 2H); MS (m/z) 626.7 [M+H]f.

Example 568

Synthesis of(S)-5-(2-(1-(2-(6-chloro-5-fluoro-1H-indol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(568)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting 6-chloro-5-fluoro-1H-indole for1H-benzo[g]indole to provide the desired compound (7 mg, 17%): ¹H NMR(400 MHz, dmso) δ 8.97 (d, 1H), 8.70 (d, 1H), 7.70-7.55 (m, 3H),7.50-7.38 (m, 4H), 7.34 (d, 1H), 7.27 (dd, 2H), 6.90 (t, 1H), 6.55 (d,2H), 6.36 (d, 1H), 5.13 (d, 1H), 4.78 (s, 2H), 3.00 (d, 2H); MS (m/z)581.9 [M+H]⁺.

Example 569

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(pyridin-2-yl)acetamido)ethyl)pyridin-3-yl)benzamide(569)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and 2-(pyridin-2-yl)acetic acid toprovide 21 mg of the desired compound in a 40% yield: ¹H NMR (400 MHz,dmso) δ 9.02 (d, 1H), 8.72-8.64 (m, 2H), 8.22 (t, 1H), 7.94 (s, 1H),7.88 (d, 1H), 7.70 (dd, 2H), 7.65 (dd, 1H), 7.59 (d, 1H), 7.53-7.38 (m,4H), 6.89 (t, 1H), 6.48 (d, 2H), 5.19 (dd, 1H), 3.84 (q, 2H), 3.06-2.91(m, 2H); MS (m/z) 473.2 [M+H]⁺.

Example 570 Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(570)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting 4-(trifluoromethyl)-1H-pyrazole for1H-benzo[g]indole to provide the desired compound (30 mg, 78%): ¹H NMR(400 MHz, dmso) δ 8.98 (d, 1H), 8.67 (dd, 1H), 8.17 (s, 1H), 7.78 (s,1H), 7.65 (s, 2H), 7.60 (dd, 1H), 7.47-7.38 (m, 3H), 7.35-7.24 (m, 1H),6.90 (t, 1H), 6.51 (d, 2H), 5.14 (dd, 1H), 4.83 (s, 2H), 2.99 (d, 2H);MS (m/z) 548.3 [M+H]⁺.

Examples 572 and 573

Synthesis of ethyl 2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoate

The title compound was prepared according to the method presented inExample 478 substituting 504B for 478B to provide the desired compound:MS (m/z) 251.2 [M+H]⁺.

Synthesis of 2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoic acid (572A)

The title compound was prepared according to the method presented inExample 478 substituting ethyl2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoate for 478C to provide thedesired compound: MS (m/z) 223.0 [M+H]⁺.

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)butanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(572B and 573)

The title compounds were prepared according to the method presented inthe synthesis of 54G substituting2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoic acid for2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid to provide the desiredcompounds (572B, peak 1 off HPLC, 8 mg, 10%; 573, peak 2 off HPLC, 10.4mg, 13%): 572B ¹H NMR (400 MHz, dmso) δ 9.08 (d, 1H), 8.63 (dd, 1H),7.85 (s, 1H), 7.68 (d, 2H), 7.61 (dd, 1H), 7.52 (dd, 1H), 7.48-7.35 (m,2H), 7.35-7.24 (m, 1H), 6.95 (t, 1H), 6.63 (d, 3H), 5.13 (dd, 1H), 4.94(t, 1H), 2.99 (dd, 2H), 1.87-1.71 (m, 2H), 0.56 (t, 3H); MS (m/z) 577.1[M+H]⁺. ¹H NMR (400 MHz, dmso) δ 9.03 (d, 1H), 8.66 (d, 1H), 7.87 (s,1H), 7.65 (s, 2H), 7.59 (dd, 1H), 7.46-7.36 (m, 3H), 7.35-7.26 (m, 1H),6.83 (t, 1H), 6.64 (s, 1H), 6.45 (d, 2H), 5.17-5.05 (m, 1H), 4.96 (t,1H), 2.97 (d, 2H), 1.96-1.85 (m, 2H), 0.67 (t, 3H); MS (m/z) 577.1[M+H]⁺.

Example 574

Synthesis of methyl 2-(4-oxo-3,4-dihydro-1H-carbazol-9(2H)-yl)acetate

The title compound was prepared according to the method presented inExample 478 substituting methyl 2-bromoacetate for 478B and2,3-dihydro-1H-carbazol-4(9H)-one for 478A to provide the desiredcompound: MS (m/z) 258.4 [M+H]⁺.

Synthesis of 2-(4-oxo-3,4-dihydro-1H-carbazol-9(2H)-yl)acetic acid(574C)

The title compound was prepared according to the method presented inExample 478 substituting methyl2-(4-oxo-3,4-dihydro-1H-carbazol-9(2H)-yl)acetate for 478C to providethe desired compound: MS (m/z) 244.3 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(4-oxo-3,4-dihydro-1H-carbazol-9(2H)-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(574D)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting2-(4-oxo-3,4-dihydro-1H-carbazol-9(2H)-yl)acetic acid for 54F to providethe desired compound (18 mg, 28): ¹H NMR (400 MHz, dmso) δ 9.12 (d, 1H),8.70 (dd, 1H), 7.93-7.87 (m, 1H), 7.69-7.58 (m, 3H), 7.53 (dd, 1H), 7.42(dd, 2H), 7.32-7.24 (m, 1H), 7.21 (d, 1H), 7.16-7.04 (m, 2H), 6.97 (t,1H), 6.65 (d, 2H), 5.16 (dd, 1H), 4.81 (s, 2H), 3.03 (d, 2H), 2.74 (d,1H), 2.68-2.57 (m, 1H), 2.34 (d, 2H), 2.00 (s, 2H); MS (m/z) 597.7[M+H]⁺.

Example 575

Synthesis of ethyl 2-(5-fluoro-2-methyl-1H-indol-1-yl)acetate

The title compound was prepared according to the method presented inExample 478 substituting ethyl 2-bromoacetate for 478B and5-fluoro-2-methyl-1H-indole for 478A to provide the desired compound.

Synthesis of 2-(5-fluoro-2-methyl-1H-indol-1-yl)acetic acid (575A)

The title compound was prepared according to the method presented inExample 478 substituting ethyl2-(5-fluoro-2-methyl-1H-indol-1-yl)acetate for 478C to provide thedesired compound: MS (m/z) 208.3 [M+H]⁺.

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(5-fluoro-2-methyl-1H-indol-1-yl)acetamido)ethyl)pyridin-3-yl)benzamide(575B)

The title compound was prepared according to the method presented in thesynthesis of 50C substituting 2-(5-fluoro-2-methyl-1H-indol-1-yl)aceticacid for 2-(5-fluoro-1H-indol-3-yl)acetic acid to provide the desiredcompound (8 mg, 13%): ¹H NMR (400 MHz, dmso) δ 8.91 (d, 1H), 8.68 (dd,1H), 7.94 (s, 1H), 7.88 (d, 1H), 7.75 (s, 1H), 7.64 (dd, 1H), 7.49-7.36(m, 4H), 7.11-7.03 (m, 2H), 6.95 (t, 1H), 6.73 (dd, 1H), 6.56 (d, 2H),6.09 (s, 1H), 5.16 (dd, 1H), 4.70 (s, 2H), 2.98 (d, 2H), 2.13 (s, 3H);MS (m/z) 543.5 [M+H]⁺.

Examples 576 and 598

Synthesis of(3-isopropyl-1H-pyrazol-5-yl)(3-methoxyazetidin-1-yl)methanone (576A)

The title compound was prepared according to the method presented inExample 482 substituting 3-methoxyazetidine for cyclopropanamine toprovide the desired compound: MS (m/z) 224.2 [M+H]⁺.

(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5-isopropyl-3-(3-methoxyazetidine-1-carbonyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(576B) and(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-isopropyl-5-(3-methoxyazetidine-1-carbonyl)-1H-pyrazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(598)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting(3-isopropyl-1H-pyrazol-5-yl)(3-methoxyazetidin-1-yl)methanone for1H-benzo[g]indole to provide the desired compounds (576B, 7 mg, 16%;598, 9 mg, 20%): 576B ¹H NMR (400 MHz, dmso) δ 8.65 (s, 1H), 8.62-8.52(m, 1H), 7.68-7.55 (m, 3H), 7.39 (dd, 3H), 7.28 (d, 1H), 6.88 (s, 1H),6.43 (d, 3H), 5.12 (d, 1H), 4.98 (s, 2H), 4.44-4.35 (m, 1H), 4.16 (s,4H), 3.18 (s, 3H), 2.95 (s, 2H), 2.85-2.74 (m, 1H), 1.13 (d, 6H); MS(m/z) 635.5 [M+H]⁺. 598 ¹H NMR (400 MHz, dmso) δ 8.79 (s, 1H), 8.66 (d,1H), 7.73-7.59 (m, 3H), 7.50 (s, 1H), 7.44-7.36 (m, 2H), 7.36-7.27 (m,1H), 6.93 (s, 1H), 6.58 (d, 2H), 6.33 (s, 1H), 5.18 (s, 1H), 4.73 (s,2H), 4.42 (s, 1H), 4.12 (d, 4H), 3.18 (s, 3H), 2.99 (d, 2H), 2.70-2.56(m, 1H), 1.00 (t, 6H); MS (m/z) 635.5 [M+H]⁺.

Example 577

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(2-(morpholinomethyl)-1H-benzo[d]imidazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(577)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting2-(2-(morpholinomethyl)-1H-benzo[d]imidazol-1-yl)acetic acid for 54F toprovide the desired compound (29 mg, 43%): ¹H NMR (400 MHz, dmso) δ 9.34(d, 1H), 8.72 (d, 1H), 7.64 (d, 4H), 7.55 (d, 1H), 7.52-7.36 (m, 3H),7.31-7.21 (m, 3H), 6.94 (t, 1H), 6.64 (d, 2H), 5.15 (d, 1H), 5.02 (s,2H), 4.45 (s, 2H), 3.69 (s, 4H), 3.05 (d, 6H); MS (m/z) 629.4 [M+H]⁺.

Example 578

Synthesis of5-(2-((1S)-2-(3,5-difluorophenyl)-1-(3-hydroxy-2-phenylpropanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(578)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting 43-hydroxy-2-phenylpropanoic acid for2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid to provide the desiredcompound (12 mg, 17%): MS (m/z) 520.4 [M+H]⁺.

Example 579

Synthesis of1-(3-methoxyazetidin-1-yl)-2-(2-methyl-1H-indol-3-yl)ethanone (579B)

The title compound was prepared according to the method presented inExample 482 substituting 2-(2-methyl-1H-indol-3-yl)acetic acid for 482Aand 3-methoxyazetidine for cyclopropanamine to provide the desiredcompound: MS (m/z) 259.4 [M+H]⁺.

Synthesis methyl2-(3-(2-(3-methoxyazetidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-1-yl)acetate

The title compound was prepared according to the method presented inExample 478 substituting methyl 2-bromoacetate for 478B and1-(3-methoxyazetidin-1-yl)-2-(2-methyl-1H-indol-3-yl)ethanone for 478Ato provide the desired compound: MS (m/z) 330.3 [M+H]⁺.

Synthesis of2-(3-(2-(3-methoxyazetidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-1-yl)aceticacid (579C)

The title compound was prepared according to the method presented inExample 478 substituting methyl2-(3-(2-(3-methoxyazetidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-1-yl)acetatefor 478C to provide the desired compound: MS (m/z) 317.9 [M+H]⁺.

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(2-(3-methoxyazetidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(579D)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting2-(3-(2-(3-methoxyazetidin-1-yl)-2-oxoethyl)-2-methyl-1H-indol-1-yl)aceticacid for 54F to provide the desired compound (3 mg, 4%): ¹H NMR (400MHz, dmso) δ 8.92 (d, 1H), 8.68 (d, 1H), 7.60 (s, 3H), 7.47 (s, 1H),7.45-7.36 (m, 2H), 7.35 (d, 1H), 7.30-7.24 (m, 1H), 7.06 (d, 1H),7.00-6.84 (m, 3H), 6.60 (s, 2H), 5.14 (s, 1H), 4.69 (s, 2H), 4.16 (s,1H), 4.07 (s, 1H), 3.92 (d, 2H), 3.87-3.79 (m, 1H), 3.40 (s, 2H), 3.11(s, 3H), 3.00 (d, 2H), 2.10 (d, 3H); MS (m/z) 670.5 [M+H]⁺.

Example 580

Synthesis of2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1-sulfonylchloride (580B)

A round bottom was charged with2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g,4.2 mmol), HCl (1.5 ml), AcOH (4.4 ml), and cool the reaction to 0° C.To the cooled stirring reaction slowly add sodium nitrate (318 mg, 4.6mmol) dissolved in H₂O (0.7 ml). Remove the ice bath and stir at RT for15 minutes and cool to 0° C. Make a mixture of CuCl₂ (373 mg, 2.2 mmol)and H₂O (0.44 ml) and add it to a cooled (0° C.) mixture of SO₂saturated in AcOH (3.7 ml). Then add the Cu mixture into the anilinemixture and allow to warm to RT over 1 hour. Ice/water was added and thesolution was filtered. The cake was dried under vacuum to give thedesired compound (1 g, 74%).

Synthesis of2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(580C)

A round bottom was charged with2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1-sulfonylchloride (1 g, 3 mmol) and 4 N ammonia in dioxane (5 ml). The mixturewas stirred at RT for 2 hours. The reaction was concentrated and usedcrude the next reaction.

Synthesis of (S)-tert-butyl2-(3,5-difluorophenyl)-1-(3-(4-fluoro-3-sulfamoylphenyl)pyridin-2-yl)ethylcarbamate(580D)

The title compound was prepared according to the method presented inExample 50 substituting2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamidefor 3-carbamoylphenylboronic acid to provide the desired compound: MS(m/z) 508.1 [M+H]⁺.

Synthesis of(S)-5-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzenesulfonamide(580E)

The title compound was prepared according to the method presented inExample 50 substituting (S)-tert-butyl2-(3,5-difluorophenyl)-1-(3-(4-fluoro-3-sulfamoylphenyl)pyridin-2-yl)ethylcarbamatefor 50B to provide the desired compound: MS (m/z) 408.2 [M+H]⁺.

Synthesis of(S)—N-(2-(3,5-difluorophenyl)-1-(3-(4-fluoro-3-sulfamoylphenyl)pyridin-2-yl)ethyl)-2-(5-fluoro-1H-indol-3-yl)acetamide(580F)

The title compound was prepared according to the method presented in thesynthesis of 50D substituting(S)-5-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzenesulfonamidefor 50C to provide the desired compound (14 mg): ¹H NMR (400 MHz, dmso)δ 8.83 (d, 1H), 8.67 (d, 1H), 7.70-7.58 (m, 3H), 7.53 (d, 1H), 7.45 (s,1H), 7.41 (dd, 1H), 7.28 (dd, 2H), 7.07 (d, 1H), 6.95 (t, 1H), 6.88 (dd,2H), 6.63 (d, 2H), 5.15 (dd, 1H), 4.60 (s, 2H), 2.99 (d, 2H); MS (m/z)583.6 [M+H]⁺.

Examples 581 and 582

Synthesis of ethyl 4-methyl-2-(methylsulfonyloxy)pentanoate (581B)

A flask is charged ethyl 2-hydroxy-4-methylpentanoate (5 g, 31 mmol),DCM (100 ml), pyridine (3 ml, 37 mmol), and methanesulfonic anhydride(6.5 g, 37 mmol). The reaction was stirred until done by TLC. Themixture was filtered to remove solids. The mother liquor was dilutedwith H₂O and extract 2× with DCM. The organic layer was dried oversodium sulfate, concentrated, and purified by flash chromatography togive the desired compound (5 g, 67%): MS (m/z) 238.9 [M+H]⁺.

Synthesis of ethyl4-methyl-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pentanoate

The title compound was prepared according to the method presented inExample 478 substituting ethyl 4-methyl-2-(methylsulfonyloxy)pentanoatefor 478B to provide the desired compound: MS (m/z) 279.2 [M+H]⁺.

Synthesis of 4-methyl-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pentanoicacid (581C)

The title compound was prepared according to the method presented inExample 478 substituting ethyl4-methyl-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pentanoate for 478C toprovide the desired compound: MS (m/z) 251.0 [M+H]⁺.

Synthesis of5-(2-((1S)-2-(3,5-difluorophenyl)-1-(4-methyl-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pentanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(581D and 582)

The title compounds were prepared according to the method presented inthe synthesis of 54G substituting4-methyl-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pentanoic acid for2-(5-(trifluoromethyl)-1H-indol-3-yl)acetic acid to provide the desiredcompounds (581D, peak 1 off HPLC, 8 mg, 10%; 582, peak 2 off HPLC, 12mg, 15%): 581D ¹H NMR (400 MHz, dmso) δ 9.19 (d, 1H), 8.63 (d, 1H), 7.84(s, 1H), 7.70 (d, 2H), 7.60 (dd, 2H), 7.45 (s, 1H), 7.39 (dd, 1H),7.37-7.28 (m, 1H), 6.99 (s, 1H), 6.69 (d, 2H), 6.62 (s, 1H), 5.19-5.02(m, 2H), 3.00 (d, 2H), 1.62 (s, 1H), 1.55-1.42 (m, 1H), 0.92 (s, 1H),0.73 (dd, 6H); MS (m/z) 605.0 [M+H]⁺. 582 ¹H NMR (400 MHz, dmso) δ 9.03(d, 1H), 8.65 (d, 1H), 7.88 (s, 1H), 7.65 (s, 2H), 7.58 (d, 1H),7.46-7.38 (m, 3H), 7.38-7.26 (m, 1H), 6.83 (d, 1H), 6.63 (s, 1H), 6.44(d, 2H), 5.12 (dd, 2H), 2.97 (d, 2H), 1.82 (s, 1H), 1.65 (d, 1H), 1.11(s, 1H), 0.77 (d, 6H); MS (m/z) 605.3 [M+H]⁺.

Example 583

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5,6-dimethyl-2H-indazol-2-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(583)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting 5,6-dimethyl-1H-indazole for1H-benzo[g]indole to provide the desired compound (5.4 mg, 15%): ¹H NMR(400 MHz, dmso) δ 8.96 (d, 1H), 8.68 (d, 1H), 7.98 (s, 1H), 7.66-7.54(m, 3H), 7.39 (dd, 4H), 7.25 (t, 2H), 6.90 (s, 1H), 6.49 (d, 2H), 5.14(d, 1H), 5.00 (s, 2H), 2.99 (d, 2H), 2.24 (d, 6H); MS (m/z) 558.4[M+H]⁺.

Example 584

Synthesis of(S)-3-(2-(1-(2-(6-(aminomethyl)-1H-indol-3-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(584)

The title compound was prepared according to the method presented in thesynthesis of 557 utilizing (S)-tert-butyl(3-(2-(1-(3-(3-carbamoylphenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethylamino)-2-oxoethyl)-1H-indol-6-yl)methylcarbamateto provide 22 mg of the desired compound in a 99% yield ¹H NMR (400 MHz,dmso) δ 10.96 (s, 1H), 8.70-8.65 (m, 1H), 8.62 (d, 1H), 8.00 (s, 2H),7.95 (s, 1H), 7.86 (d, 1H), 7.75 (s, 1H), 7.61 (dd, 1H), 7.41 (ddd, 4H),7.30 (d, 1H), 7.06 (s, 1H), 6.91 (d, 2H), 6.50 (d, 2H), 5.18 (dd, 2H),4.03 (d, 2H), 3.47 (d, 2H), 2.95 (d, 2H); MS (m/z) 540.2 [M+H]⁺.

Example 585

Synthesis of(S)-5-(2-(1-(2-(5-chloro-1H-indol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)-2-fluorobenzamide(585)

The title compound was prepared according to the method presented in thesynthesis of 56B substituting 5-chloro-1H-indole for 1H-benzo[g]indoleto provide the desired compound (24 mg, 61%): ¹H NMR (400 MHz, dmso) δ8.96 (d, 1H), 8.69 (d, 1H), 7.67-7.57 (m, 3H), 7.50 (s, 2H), 7.44-7.37(m, 2H), 7.32-7.24 (m, 1H), 7.21 (d, 1H), 7.04 (d, 1H), 6.97 (d, 2H),6.61 (d, 2H), 6.32 (d, 1H), 5.13 (s, 1H), 4.77 (s, 2H), 3.01 (d, 2H); MS(m/z) 563.9 [M+H]⁺.

Example 587

Synthesis of ethyl 2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)butanoate(587A)

The title compound was prepared according to the method presented inExample 478 substituting 540A for 478A and 504B for 478B to provide thedesired compound: MS (m/z) 261.3 [M+H]⁺.

Synthesis of 2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)butanoic acid(587B)

The title compound was prepared according to the method presented inExample 478 substituting ethyl2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)butanoate for 478C to providethe desired compound: MS (m/z) 233.3 [M+H]⁺.

Synthesis of 5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)butanamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(587C)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting2-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)butanoic acid for 54F toprovide the desired compound (11 mg, 14%): MS (m/z) 586.5 [M+H]⁺.

Example 588

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(6-hydroxy-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(588)

The title compound was prepared according to the method presented inExample 56 substituting 1H-indazol-6-ol for 1H-benzo[g]indole to providethe desired compound (10 mg, 16%): ¹H NMR (400 MHz, dmso) δ 8.70-8.63(m, 1H), 8.56 (d, 1H), 7.90 (s, 1H), 7.67 (d, 2H), 7.63-7.54 (m, 2H),7.49 (d, 1H), 7.43-7.37 (m, 2H), 7.32 (dd, 1H), 6.85 (dd, 2H), 6.75 (dd,1H), 6.49 (d, 2H), 5.22 (dd, 1H), 4.46 (d, 2H), 3.09-2.91 (m, 3H); MS(m/z) 546.2 [M+H]⁺.

Example 589

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(589)

The title compound was prepared according to the method presented in thesynthesis of 54G utilizing 54B and2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid toprovide 40 mg of the desired compound in a 50% yield: ¹H NMR (400 MHz,dmso) δ 8.92 (d, 1H), 8.67 (dd, 1H), 7.66 (s, 1H), 7.62 (dd, 1H), 7.49(dd, 1H), 7.41 (dd, 2H), 7.36-7.25 (m, 1H), 6.92 (t, 1H), 6.57 (d, 2H),5.17 (dd, 1H), 4.70 (s, 3H), 3.07-2.94 (m, 2H), 2.41 (s, 2H), 2.32 (d,1H), 2.17 (d, 1H), 1.59 (d, 4H); MS (m/z) 603.3 [M+H]⁺.

Example 590

Synthesis of5-(2-((1S)-2-(3,5-difluorophenyl)-1-(2-(dimethylamino)-2-(4-fluorophenyl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(590)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting 2-(dimethylamino)-2-(4-fluorophenyl)aceticacid for 54F to provide the desired compound (the second peak off HPLC,4 mg, 6%): ¹H NMR (400 MHz, dmso) δ 10.15-10.06 (m, 1H), 9.58 (s, 1H),8.68 (d, 1H), 7.77-7.66 (m, 2H), 7.63 (s, 1H), 7.50 (s, 1H), 7.48-7.36(m, 2H), 7.36-7.28 (m, 2H), 7.18 (t, 2H), 6.78 (s, 1H), 6.35 (d, 2H),5.20 (s, 1H), 4.78 (s, 1H), 2.91 (d, 2H), 2.58 (s, 3H), 2.33 (s, 3H); MS(m/z) 551.3 [M+H]⁺.

Example 591

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(6-(trifluoromethyl)-1H-indol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(591)

The title compound was prepared according to the method presented inExample 56 substituting 6-(trifluoromethyl)-1H-indole for1H-benzo[g]indole to provide the desired compound (15 mg, 36%): ¹H NMR(400 MHz, dmso) δ 9.02 (d, 1H), 8.67 (d, 1H), 7.67 (d, 1H), 7.61 (d,2H), 7.58 (s, 2H), 7.45 (d, 1H), 7.40 (t, 3H), 7.24 (t, 2H), 6.86 (s,11H), 6.54 (d, 2H), 6.49 (d, 1H), 5.13 (d, 1H), 4.89 (s, 2H), 3.00 (d,2H); MS (m/z) 598.1 [M+H]⁺.

Example 592

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(5,6-dimethyl-1H-indol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(592)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting 2-phenylacetic acid for 54F to provide thedesired compound (23 mg, 44%): ¹H NMR (400 MHz, dmso) δ 8.73 (d, 1H),8.66 (dd, 1H), 7.65 (d, 2H), 7.59 (dd, 1H), 7.50 (dd, 1H), 7.39 (dd,2H), 7.34-7.24 (m, 1H), 7.14 (dq, 3H), 7.04 (d, 2H), 6.90 (t, 1H), 6.56(d, 2H), 5.10 (dd, 1H), 3.34 (dd, 2H), 2.98 (d, 2H); MS (m/z) 490.6[M+H]⁺.

Example 593

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(5-hydroxy-6-methyl-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(593)

A round bottom was charged with 536I (30 mg, 0.05 mmol), dioxane (5 ml),Pd/C (10 mg), H2NaO2P•H2O (60 mg, 0.6 mmol), and H₂O (1 ml). Theresulting mixture was stirred at 95° C. until done as indicated byLC/MS. The reaction mixture was cooled to RT and filtered over a plug ofcelite, rinsing with ethyl acetate. The layers were partitioned and theorganic layer was dried over sodium sulfate, filtered, concentrated andpurified by HPLC to give the desired compound (16 mg, 66%): ¹H NMR (400MHz, dmso) δ 10.32 (s, 1H), 8.66-8.57 (m, 1H), 8.35 (d, 1H), 7.96 (s,1H), 7.86 (d, 1H), 7.69 (s, 1H), 7.58 (dd, 1H), 7.44 (t, 1H), 7.36 (dt,3H), 6.95 (s, 1H), 6.90-6.80 (m, 2H), 6.76 (s, 1H), 6.37 (d, 2H),5.27-5.16 (m, 1H), 3.37 (s, 2H), 2.91 (d, 2H), 2.14 (s, 3H); MS (m/z)541.2 [M+H]⁺.

Example 594

Synthesis of ethyl 2-(5,6-difluoro-1H-indol-1-yl)acetate

The title compound was prepared according to the method presented inExample 478 substituting ethyl 2-bromoacetate for 478B and5,6-difluoro-1H-indole for 478A to provide the desired compound.

Synthesis of 2-(5,6-difluoro-1H-indol-1-yl)acetic acid (594A)

The title compound was prepared according to the method presented inExample 478 substituting ethyl 2-(5,6-difluoro-1H-indol-1-yl)acetate for478C to provide the desired compound: MS (m/z) 212.2 [M+H]⁺.

Synthesis of(S)-3-(2-(1-(2-(5,6-difluoro-1H-indol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)pyridin-3-yl)benzamide(594B)

The title compound was prepared according to the method presented in thesynthesis of SOD substituting 2-(5,6-difluoro-1H-indol-1-yl)acetic acidfor 2-(5-fluoro-1H-indol-3-yl)acetic acid to provide the desiredcompound (27 mg, 44%): ¹H NMR (400 MHz, dmso) δ 8.92 (d, 1H), 8.68 (d,1H), 7.94 (s, 1H), 7.88 (d, 1H), 7.73 (s, 1H), 7.64 (d, 1H), 7.52-7.35(m, 5H), 7.19 (d, 1H), 7.15 (dd, 1H), 6.88 (t, 1H), 6.52 (d, 2H), 6.34(d, 1H), 5.18 (dd, 1H), 4.75 (s, 2H), 3.05-2.94 (m, 2H); MS (m/z) 547.6[M+H]⁺.

Example 595

Synthesis ofN—((S)-1-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(595)

The title compound was prepared according to the method presented in thesynthesis of 61F substituting 122E for 61C to provide the desiredcompound (18 mg, 17%): ¹H NMR (400 MHz, cd₃od) δ 8.47 (d, 1H), 7.77 (s,1H), 7.58 (s, 1H), 7.41 (d, 1H), 7.32 (d, 1H), 7.19 (dd, 1H), 6.44 (d,1H), 6.38 (d, 1H), 6.01 (d, 2H), 5.15-5.02 (m, 1H), 4.49-4.41 (m, 2H),2.82 (d, 3H), 2.55 (d, 1H), 2.41 (dd, 1H), 1.82 (s, 2H), 0.83 (d, 2H);MS (m/z) 579.4 [M+H]⁺.

Example 596

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(5-(trifluoromethyl)-1H-indol-3-yl)acetamido)ethyl)pyridin-3-yl)benzamide(596)

The title compound was prepared according to the method presented in thesynthesis of 50D utilizing 50C and 54F to provide 23 mg of the desiredcompound in a 35% yield: ¹H NMR (400 MHz, dmso) δ 11.24 (s, 1H), 8.69(d, 1H), 8.63 (dd, 1H), 7.93 (s, 1H), 7.86 (d, 1H), 7.81 (s, 1H), 7.71(s, 1H), 7.60 (dd, 1H), 7.48-7.34 (m, 4H), 7.28 (d, 1H), 7.20 (s, 1H),6.82 (t, 1H), 6.43 (d, 2H), 5.19 (dd, 2H), 3.53 (s, 2H), 2.94 (d, 2H);MS (m/z) 579.2 [M+H]⁺.

Example 597

Synthesis of(S)—N-(1-(3-(4-chlorophenyl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5-fluoro-2-methyl-1H-indol-3-yl)acetamide(597)

The title compound was prepared according to the method presented in thesynthesis of 36F utilizing 36E and 517D to provide 13 mg of the desiredcompound in a 21% yield: ¹H NMR (400 MHz, dmso) δ 10.76 (s, 1H), 8.63(dd, 1H), 8.59 (d, 1H), 7.53 (dd, 1H), 7.44-7.32 (m, 3H), 7.23 (d, 2H),7.11 (dd, 1H), 7.06 (dd, 1H), 6.91 (t, 1H), 6.71 (td, 1H), 6.42 (d, 2H),5.11 (dd, 1H), 3.45-3.29 (m, 2H), 3.00-2.82 (m, 2H), 2.20 (s, 3H); MS(m/z) 534.6 [M+H]⁺.

Example 599

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(2-(trifluoromethyl)-1H-indol-1-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(599)

The title compound was prepared according to the method presented inExample 56 substituting 2-(trifluoromethyl)-1H-indole for1H-benzo[g]indole to provide the desired compound (14 mg, 34%): ¹H NMR(400 MHz, dmso) δ 8.97 (d, 1H), 8.70 (d, 1H), 7.60 (dd, 4H), 7.49-7.36(m, 3H), 7.30-7.18 (m, 3H), 7.10 (t, 1H), 7.01 (s, 1H), 6.94 (s, 1H),6.58 (d, 2H), 5.13 (d, 1H), 4.88 (s, 2H), 3.00 (d, 2H); MS (m/z) 597.5[M+H]⁺.

Example 600

Synthesis of(S)-5-(2-(2-(3,5-difluorophenyl)-1-(2-(2-methyl-4H-benzo[4,5]imidazo[1,2-b][1,2,4]triazol-4-yl)acetamido)ethyl)pyridin-3-yl)-2-fluorobenzamide(600)

The title compound was prepared according to the method presented in thesynthesis of 54G substituting2-(2-methyl-4H-benzimidazo[1,2-b][1,2,4]triazol-4-yl)acetic acid. for54F to provide the desired compound (12 mg, 25%): ¹H NMR (400 MHz, dmso)δ 9.11 (d, 1H), 8.70 (d, 1H), 7.63 (dd, 4H), 7.49-7.35 (m, 3H),7.29-7.18 (m, 4H), 6.94 (s, 1H), 6.58 (d, 2H), 5.15 (d, 1H), 4.82 (s,2H), 3.03 (d, 2H), 2.32 (s, 3H); MS (m/z) 584.6 [M+H]⁺.

Example 601

Synthesis of(S)-3-(2-(2-(3,5-difluorophenyl)-1-(2-(3-methoxyphenyl)acetamido)ethyl)pyridin-3-yl)benzamide(601)

The title compound was prepared according to the method presented in thesynthesis of SOD utilizing 50C and 2-(3-methoxyphenyl)acetic acid toprovide 18 mg of the desired compound in a 40% yield: ¹H NMR (400 MHz,dmso) δ 8.71 (d, 1H), 8.66 (d, 1H), 7.94 (s, 1H), 7.88 (d, 1H), 7.75 (s,1H), 7.62 (dd, 1H), 7.47 (t, 1H), 7.44-7.37 (m, 3H), 7.06 (t, 1H), 6.88(t, 1H), 6.68 (d, 1H), 6.65 (s, 1H), 6.61 (d, 1H), 6.48 (d, 2H), 5.16(d, 1H), 3.64 (s, 3H), 3.32 (dd, 2H), 2.95 (d, 2H); MS (m/z) 502.2[M+H]⁺.

Example 602

The following illustrate representative pharmaceutical dosage forms,containing a compound of formula I (‘Compound X’), for therapeutic orprophylactic use in humans

(i) Tablet 1 mg/tablet Compound X= 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0

(ii) Tablet 2 mg/tablet Compound X= 20.0 Microcrystalline cellulose410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0500.0

(iii) Capsule mg/capsule Compound X= 10.0 Colloidal silicon dioxide 1.5Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0

(iv) Injection 1 (1 mg/ml) mg/ml Compound X = (free acid form) 1.0Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodiumchloride 4.5 1.0N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL

(v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethyleneglycol 400 200.0 1.0N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 ml.

(vi) Aerosol mg/can Compound X= 20.0 Oleic acid 10.0Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0Dichlorotetrafluoroethane 5,000.0

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is: 1-49. (canceled)
 50. A method for treating an HIVinfection in a human, comprising administering a compound of formula I:

or a pharmaceutically acceptable salt thereof, to the human, wherein: Ais pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein anypyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl of A is substitutedwith one Z¹ group and optionally substituted with 1, 2, or 3 Z² groups;B is absent; or B is —O⁻ and the nitrogen to which the —O⁻ group isattached is N⁺; W is —CR^(3a)R^(3b)—; R¹ is a bicyclic-heteroaryl,tricyclic-heteroaryl, bicyclic-heterocycle or tricyclic-heterocycle,wherein any bicyclic-heteroaryl, tricyclic-heteroaryl,bicyclic-heterocycle or tricyclic-heterocycle of R¹ is optionallysubstituted with 1, 2, 3, 4, or 5 Z³ groups; R² is a 6-membered aryl,5-membered heteroaryl or 6-membered heteroaryl, wherein any 6-memberedaryl, 5-membered heteroaryl or 6-membered heteroaryl of R² is optionallysubstituted with 1, 2, or 3 Z⁴ groups; each R^(3a) and R^(3b) isindependently selected from H, (C₁-C₆)alkyl, (C₁-C₃)haloalkyl,(C₁-C₆)heteroalkyl, heterocyclyl(C₁-C₆)alkyl-; each Z¹ is independentlyselected from (C₂-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₇)carbocycle, (C₆-C₂₀)aryl, heteroaryl, heterocycle and —OR_(n1),wherein any (C₃-C₇)carbocycle, (C₆-C₂₀)aryl, heteroaryl and heterocycleof Z¹ is optionally substituted with 1, 2, 3, 4, or 5 Z^(1a) or Z^(1b)groups and wherein any (C₂-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynylof Z¹ is optionally substituted with 1, 2, 3, 4, or 5 Z^(1a) groups;each Z^(1a) is independently selected from (C₃-C₇)carbocycle,(C₆-C₂₀)aryl, heteroaryl, heterocycle, halogen, —CN, —OR_(n2),—OC(O)R_(p2), —OC(O)NR_(q2)R_(r2), —SR_(n2), —S(O)R_(p2), —S(O)₂OH,—S(O)₂R_(p2), —S(O)₂NR_(q2)R_(r2), —NR_(q2)R_(r2), —NR_(n2)COR_(p2),—NR_(n2)CO₂R_(p2), —NR_(n2)CONR_(q2)R_(r2), —NR_(n2)S(O)₂R_(p2),—NR_(n2)S(O)₂OR_(p2), —NR_(n2)S(O)₂NR_(q2)R_(r2), NO₂, —C(O)R_(n2),—C(O)OR_(n2), —C(O)NR_(q2)R_(r2) and —S(O)₂NR_(n2)COR_(p2), wherein any(C₃-C₇)carbocycle, (C₆-C₂₀)aryl, heteroaryl and heterocycle of Z^(1a) isoptionally substituted with 1, 2, 3, 4, or 5 Z^(1c) or Z^(1d) groups;each Z^(1b) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl, wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z^(1b) is optionally substituted with 1, 2, 3, 4, or 5Z^(1c) groups; each Z^(1c) is independently selected from(C₃-C₇)carbocycle, (C₆-C₂₀)aryl, heteroaryl, heterocycle, halogen, —CN,—OR_(n3), —OC(O)R_(p3), —OC(O)NR_(q3)R_(r3), —SR_(n3), —S(O)R_(p3),—S(O)₂OH, —S(O)₂R_(p3), —S(O)₂NR_(q3)R_(r3), —NR_(q3)R_(r3),—NR_(n3)COR_(p3), —NR_(n3)CO₂R_(p3), —NR_(n3)CONR_(q3)R_(r3),—NR_(n3)S(O)₂R_(p3), —NR_(n3)S(O)₂OR_(p3), —NR_(n3)S(O₂NR_(q3)R_(r3),NO₂, —C(O)R_(n3), —C(O)OR_(n3), —C(O)NR_(q3)R_(r3), (C₆-C₂₀)haloaryl,haloheteroaryl, haloheterocycle and (C₁-C₈)heteroalkyl; each Z^(1d) isindependently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyland (C₁-C₈)haloalkyl; each R_(n1) is independently selected from(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle,heterocycle, heteroaryl and (C₆-C₂₀)aryl, wherein any (C₃-C₇)carbocycle,(C₆-C₂₀)aryl, heteroaryl and heterocycle of R_(n1) is optionallysubstituted with 1, 2, 3, 4, or 5 Z^(1a) or Z^(1b) groups, and whereinany (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(n1) isoptionally substituted with 1, 2, 3, 4, or 5 Z^(1a) groups; each R_(n2)is independently selected from H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and(C₆-C₂₀)aryl, wherein any (C₃-C₇)carbocycle, (C₆-C₂₀)aryl, heteroaryland heterocycle of R_(n2) is optionally substituted with 1, 2, 3, 4, or5 Z^(1c) or Z^(1d) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of R_(n2) is optionally substituted with 1, 2, 3, 4,or 5 Z^(1c) groups; each R_(p2) is independently selected from(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle,heterocycle, heteroaryl and (C₆-C₂₀)aryl, wherein any (C₃-C₇)carbocycle,(C₆-C₂₀)aryl, heteroaryl and heterocycle of R_(p2) is optionallysubstituted with 1, 2, 3, 4, or 5 Z^(1c) or Z^(1d) groups, and whereinany (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(p2) isoptionally substituted with 1, 2, 3, 4, or 5 Z^(1c) groups; R_(q2) andR_(r2) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl and (C₆-C₂₀)aryl, wherein any (C₃-C₇)carbocycle,(C₆-C₂₀)aryl, heteroaryl and heterocycle of R_(q2) or R_(r2) isoptionally substituted with 1, 2, 3, 4, or 5 Z^(1c) or Z^(1d) groups,and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl ofR_(q2) or R_(r2) is optionally substituted with 1, 2, 3, 4, or 5 Z^(1c)groups, or R_(q2) and R_(r2) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with 1, 2, 3, 4 or 5Z^(1c) or Z^(1d) groups; each R_(n3) is independently selected from H,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle,heterocycle, heteroaryl, (C₆-C₂₀)aryl, (C₆-C₂₀)haloaryl, haloheteroaryl,haloheterocycle, (C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl; each R_(p3) isindependently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl,(C₆-C₂₀)aryl, (C₆-C₂₀)haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl; R_(q3) and R_(r3) are eachindependently selected from H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl,(C₆-C₂₀)aryl, haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R_(q3) and R_(r3) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle; each Z² is independently selected from (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, halogen, CN, OH and —O(C₁-C₆)alkyl;each Z³ is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, (C₆-C₂₀)aryl, halogen, —CN, —OR_(n4),—S(O)R_(p4), —NR_(n4)CO₂R_(p4), —NR_(n4)S(O)₂R_(p4), —C(O)R_(n4),—C(O)OR_(n4), —C(O)NR_(q4)R_(r4) and —B(OR_(q4))(OR_(r4)) wherein any(C₃-C₇)carbocycle and (C₆-C₂₀)aryl of Z³ is optionally substituted with1, 2, 3, 4, or 5 Z^(3a) or Z^(3b) groups, and wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl and (C₂-C₈)alkynyl of Z³ is optionally substituted with1, 2, 3, 4, or 5 Z^(3a) groups; each Z^(3a) is independently selectedfrom (C₃-C₇)carbocycle, (C₆-C₂₀)aryl, heteroaryl, heterocycle, halogen,—CN, —OR_(n5), —OC(O)R_(p5), —OC(O)NR_(q5)R_(r5), —SR_(n5), —S(O)R_(p5),—S(O)₂₀H, —S(O)₂R_(p5), —S(O)₂NR_(q5)R_(r5), —NR_(q5)R_(r5),—NR_(n5)COR_(p5), —NR_(n5)CO₂R_(p5), —NR_(n5)CONR_(q5)R_(r5),—NR_(n5)S(O)₂R_(p5), —NR_(n5)S(O)₂OR_(p5), —NR_(n5)S(O)₂NR_(q5)R_(r5),NO₂, —C(O)R_(n5), —C(O)OR_(n5), and —C(O)NR_(q5)R_(r5), wherein any(C₃-C₇)carbocycle, (C₆-C₂₀)aryl, heteroaryl and heterocycle of Z^(3a) isoptionally substituted with 1, 2, 3, 4, or 5 Z^(3c) or Z^(3d) groups;each Z^(3b) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl, wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and(C₂-C₈)alkynyl of Z^(3b) is optionally substituted with 1, 2, 3, 4, or 5Z^(3c) groups; each Z^(3c) is independently selected from(C₃-C₇)carbocycle, (C₆-C₂₀)aryl, heteroaryl, heterocycle, halogen, —CN,—OR_(n6), —OC(O)R_(p6), —OC(O)NR_(q6)R_(r6), —SR_(n6), —S(O)R_(p6),—S(O)₂₀H, —S(O)₂R_(p6), —S(O)₂NR_(q6)R_(r6), —NR_(q6)R_(r6),—NR_(n6)COR_(p6), —NR_(n6)CO₂R_(p6), —NR_(n6)CONR_(q6)R_(r6),—NR_(n6)S(O)₂R_(p6), —NR_(n6)S(O)₂OR_(p6), —NR_(n6)S(O)₂ NR_(q6)R_(r6),NO₂, —C(O)R_(n6), —C(O)OR_(n6), —C(O)NR_(q6)R_(r6), (C₆-C₂₀)haloaryl,haloheteroaryl, haloheterocycle and (C₁-C₈)heteroalkyl; each Z^(3d) isindependently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, and (C₁-C₈)haloalkyl; each R_(n4) is independentlyselected from H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₇)carbocycle, heterocycle, heteroaryl and (C₆-C₂₀)aryl, wherein any(C₃-C₇)carbocycle, (C₆-C₂₀)aryl, heteroaryl and heterocycle of R_(n4) isoptionally substituted with 1, 2, 3, 4, or 5 Z^(3a) or Z^(3b) groups,and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl ofR_(n4) is optionally substituted with 1, 2, 3, 4, or 5 Z^(3a) groups;each R_(p4) is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and(C₆-C₂₀)aryl, wherein any (C₃-C₇)carbocycle, (C₆-C₂₀)aryl, heteroaryl,or heterocycle of R_(p4) is optionally substituted with 1, 2, 3, 4, or 5Z^(3a) or Z^(3b)groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl or(C₂-C₈)alkynyl of R_(p4) is optionally substituted with 1, 2, 3, 4, or 5Z^(3a) groups; R_(q4) and R_(r4) are each independently selected from H,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle,heterocycle, heteroaryl and (C₆-C₂₀)aryl, wherein any (C₃-C₇)carbocycle,(C₆-C₂₀)aryl, heteroaryl and heterocycle of R_(q4) or R_(r4) isoptionally substituted with one or more Z^(3a) or Z^(3b) groups, andwherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(q4) orR_(r4) is optionally substituted with 1, 2, 3, 4, or 5 Z^(3a) groups, orR_(q4) and R_(r4) together with the nitrogen to which they are attachedform a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or 7-memberedheterocycle is optionally substituted with 1, 2, 3, 4, or 5 Z^(3a) orZ^(3b) groups; each R_(n5) is independently selected from H,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle,heterocycle, heteroaryl and (C₆-C₂₀)aryl, wherein any (C₃-C₇)carbocycle,(C₆-C₂₀)aryl, heteroaryl and heterocycle of R_(n5) is optionallysubstituted with 1, 2, 3, 4, or 5 Z^(3c) or Z^(3d) groups, and whereinany (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl of R_(n5) isoptionally substituted with 1, 2, 3, 4, or 5 Z^(3c) groups; each R_(p5)is independently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl and(C₆-C₂₀)aryl, wherein any (C₃-C₇)carbocycle, (C₆-C₂₀)aryl, heteroaryland heterocycle of R_(p5) is optionally substituted with 1, 2, 3, 4, or5 Z^(3c) or Z^(3d) groups, and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyland (C₂-C₈)alkynyl of R_(p5) is optionally substituted with 1, 2, 3, 4,or 5 Z^(3c) groups; R_(q5) and R_(r5) are each independently selectedfrom H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle,heterocycle, heteroaryl and (C₆-C₂₀)aryl, wherein any (C₃-C₇)carbocycle,(C₆-C₂₀)aryl, heteroaryl and heterocycle of R_(q5) or R_(r5) isoptionally substituted with 1, 2, 3, 4, or 5 Z^(3c) or Z^(3d) groups,and wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl and (C₂-C₈)alkynyl ofR_(q5) or R_(r5) is optionally substituted with 1, 2, 3, 4, or 5 Z^(3c)groups, or R_(q5) and R_(r5) together with the nitrogen to which theyare attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or7-membered heterocycle is optionally substituted with 1, 2, 3, 4, or 5Z^(3c) or Z^(3d) groups; each R_(n6) is independently selected from H,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle,heterocycle, heteroaryl, (C₆-C₂₀)aryl, (C₆-C₂₀)haloaryl, haloheteroaryl,haloheterocycle, (C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl; each R_(p6) isindependently selected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl,(C₆-C₂₀)aryl, (C₆-C₂₀)haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl; R_(q6) and R_(r6) are eachindependently selected from H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle, heteroaryl,(C₆-C₂₀)aryl, (C₆-C₂₀)haloaryl, haloheteroaryl, haloheterocycle,(C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl, or R_(q6) and R_(r6) togetherwith the nitrogen to which they are attached form a 5, 6 or 7-memberedheterocycle; each Z⁴ is independently selected from (C₃-C₇)carbocycle,halogen, methyl and —CN; each Z⁴ is independently selected from of(C₃-C₇)carbocycle, (C₆-C₂₀)aryl, heteroaryl, heterocycle, halogen, —CN,—OR_(n9), —OC(O)R_(p9), —OC(O)NR_(q9)R_(r9), —SR_(n9), —S(O)R_(p9),—S(O)₂OH, —S(O)₂R_(p9), —S(O)₂NR_(q9)R_(r9), —NR_(q9)R_(r9),—NR_(n9)COR_(p9), —NR_(n9)CO₂R_(p9), —NR_(n9)CONR_(q9)R_(r9),—NR_(n9)S(O)₂R_(p9), —NR_(n9)S(O)₂OR_(p9), —NR_(n9)S(O)₂ NR_(q9)R_(r9),NO₂, —C(O)R_(n9), —C(O)OR_(n9), —C(O)NR_(q9)R_(r9), (C₆-C₂₀)haloaryl,haloheteroaryl, haloheterocycle and (C₁-C₈)heteroalkyl; each Z^(4d) isindependently selected from of (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl and (C₁-C₈)haloalkyl; each R_(r9) is independentlyselected from H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₇)carbocycle, heterocycle, heteroaryl, (C₆-C₂₀)aryl,(C₆-C₂₀)haloaryl, haloheteroaryl, haloheterocycle, (C₁-C₈)haloalkyl and(C₁-C₈)heteroalkyl; each R_(p9) is independently selected from(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle,heterocycle, heteroaryl, (C₆-C₂₀)aryl, (C₆-C₂₀)haloaryl, haloheteroaryl,haloheterocycle, (C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl; and R_(q9) andR_(r9) are each independently selected from H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₇)carbocycle, heterocycle,heteroaryl, (C₆-C₂₀)aryl, (C₆-C₂₀)haloaryl, haloheteroaryl,haloheterocycle, (C₁-C₈)haloalkyl and (C₁-C₈)heteroalkyl; or R_(q9) andR_(r9) together with the nitrogen to which they are attached form a 5, 6or 7-membered heterocycle.
 51. The method of claim 50, wherein thecompound of formula I is a compound of formula Icc:

or a pharmaceutically acceptable salt thereof.
 52. The method of claim50, wherein each R^(3a) and R^(3b) is H.
 53. The method of claim 50,wherein A is selected from:

wherein each Z^(2a) is independently selected from H and Z².
 54. Themethod of claim 50, wherein Z¹ is selected from (C₆-C₂₀)aryl, heteroaryland heterocycle, wherein any (C₆-C₂₀)aryl, heteroaryl, or heterocycle ofZ¹ is optionally substituted with 1, 2, 3, 4, or 5 Z¹a or Z^(1b) groups.55. The method of claim 50, wherein each Z^(1a) is independentlyselected from (C₆-C₂₀)aryl, heteroaryl, heterocycle, (C₃-C₇)carbocycle,halogen, —CN, —OR_(n2), —S(O)₂R_(p2), —S(O)₂NR_(q2)R_(r2),—NR_(q2)R_(r2), —NR_(n2)COR_(p2), —NR_(n2)CO₂R_(p2),—NR_(n2)CONR_(q2)R_(r2), —NR_(n2)S(O)₂R_(p2), —C(O)R_(n2) and—C(O)NR_(q2)R_(r2), wherein any (C₆-C₂₀)aryl, heteroaryl, heterocycleand (C₃-C₇)carbocycle of Z^(1a) is optionally substituted with 1, 2, 3,4, or 5 Z^(1c) or Z^(1d) groups; and each Z^(1b) is independentlyselected from (C₁-C₈)alkyl and (C₂-C₈)alkynyl, wherein any (C₁-C₈)alkyland (C₂-C₈)alkynyl of Z^(1b) is optionally substituted with 1, 2, 3, 4,or 5 Z^(1c) groups.
 56. The method of claim 50, wherein R² is a6-membered aryl wherein the 6-membered aryl is optionally substitutedwith 1, 2, or 3 Z⁴ groups.
 57. The method of claim 50, wherein R² isselected from:


58. The method of claim 50, wherein R¹ is bicyclic-heteroaryl,tricyclic-heteroaryl, bicyclic-heterocycle or tricyclic-heterocycle,wherein any bicyclic-heteroaryl, tricyclic-heteroaryl,bicyclic-heterocycle or tricyclic-heterocycle of R¹ contains at leastone partially unsaturated ring, and wherein any bicyclic-heteroaryl,tricyclic-heteroaryl, bicyclic-heterocycle or tricyclic-heterocycle ofR¹ is optionally substituted with 1, 2, 3, 4, or 5 Z³ groups.
 59. Themethod of claim 50, wherein each Z³ is independently selected frommethyl, trifluoromethyl, hydroxy, methoxy, benzyloxy, fluoro, —NHSO₂CH₃,2-hydroxyprop-2yl, difluoromethyl and amino.
 60. The method of claim 50,wherein the compound of formula I is selected from:

or a pharmaceutically acceptable salt thereof.
 61. The method of claim50, comprising administering to the human in need thereof atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more additional therapeuticagents selected from the group consisting HIV protease inhibitingcompounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside inhibitors of reverse transcriptase, HIV nucleotideinhibitors of reverse transcriptase, HIV integrase inhibitors, gp41inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsidpolymerization inhibitors, and other drugs for treating HIV, andcombinations thereof.